Annual Report 2016 From disease mechanisms to clinical practice
NORDIC EMBL PARTNERSHIP FOR MOLECULAR MEDICINE
Contents
Overview from the Director
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NCMM History in Brief
Merger between NCMM and BiO Welcome to the new Assistant Director
6 6 7
NCMM Research
8
NCMM Group Leaders 8 Group Taskén – Signalling Networks in Health and Disease 10 Group Mills – Prostate Cancer 14 Group Morth – Membrane Transport 18 Group Hurtado – Breast Cancer 22 Group Staerk – Stem Cells 26 Group Mathelier - Computational Biology and Gene Regulation 30 Group Lopez-Aviles - Cell Cycle Regulations 34 Group Esguerra – Chemical Neuroscience 38 Group Sekulic – Structural Biology and Chromatin 40 Group Gözen – Bionanotechnology and Membrane Systems 44
NCMM Associate Investigators
48
Research Collaborations 50 From Disease Mechanisms to Clinical Practice
52
Research Highlights
53
News and Events 2016
56 57 60
King Olav V Prize 2016 Network Meeting 2017
NCMM PhD Dissertations NCMM Board
61 62
Scientific Advisory Board
64
NCMM Funding
65
NCMM-affiliated Publications and Press items
66
Core Facilities
72
Personnel
74
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An overview from the Director 2016 saw a number of important developments for NCMM, including the merger with the Biotechnology Centre, and the appointment of three new Group Leaders. NCMM Director, Professor Kjetil Taskén, answers some questions on the highlights and developments at NCMM during 2016/Q1 2017:
What were your highlights of 2016?
2016 and early 2017 was a busy, but very successful time for NCMM. In our seventh year, NCMM has grown and further built on its successes to become an even more established and important presence in the European molecular research world. For me, as Director, some highlights from 2016 and Q1 2017 were: 1. The merger of NCMM and the Biotechnology Centre. This was first initiated in 2016, and came fully into effect at the start of 2017. The merger gives us a more robust centre, with larger scientific mass, and also a good basis with infrastructure and technology platforms, as well as an even stronger international network. NCMM will be home to 11 research groups and technology platforms across two branches; NCMM Translational Research and NCMM Biotechnology, known collectively as NCMM 2. Securing the funding of NOR-OPENSCREEN as a national infrastructure for chemical biology. Funding of 33 mNOK, headed by UiO (NCMM), and with University of Tromsø (UiT), SINTEF, and University of Bergen (UiB) as partners from 2016; and to join EU-OPENSCREEN as a founding member when it is established in 2017 3. Norway entering EATRIS as a full member from 2016, headed by NCMM and with UiO, UiB, NTNU, UiT, and all four Regional Health Authorities of Norway; Northern, Southern and Eastern, Western, and Central, as partners. This was approved by the Research Council of Norway and the Department of Health and Social Services 4. A very successful EMBL Partnership meeting in June 2016 in Heidelberg 5. The first NCMM Network Meetings in January 2016, and a second Network meeting in February 2017. NCMM has also added to its research expertise and talent base, by appointing three new Group Leaders, Anthony Mathelier, Nikolina Sekulic, and Irep Gözen. I greatly look forward to seeing these three new groups grow and develop over the coming years. Furthermore, NCMM has appointed an Assistant Director,
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Hartmut Luecke, a structural biologist. He is currently based at University of California, Irvine, where he is the director of the university’s Centre for Biomembrane Systems and a Professor of Biochemistry. Professor Luecke will officially join NCMM in November 2017. It was also a really successful year for NCMM in terms of outputs, widening and strengthening our collaborations, and growth and consolidation of external funding. NCMM Group Leaders report 60-plus national collaborations, which just goes to show the strength and breadth of molecular research taking place at NCMM, and the importance and relevance of this research on a national level. Our Group Leaders are also increasingly collaborating with researchers all over the globe; this year 50-plus international collaborations have been reported.
What do you see as the main areas of progress and success for the Nordic EMBL Partnership?
The Nordic EMBL Partnership is working very effectively; the four centres continue to develop, and the attendance at our annual gatherings and our many other interactions continue to increase. MIMS is now, as the first of the four centres, starting its 3rd five-year funding period, while DANDRITE has been evaluated in its first five-year period, with extension approved by the Board for a further five years. The support from NordForsk also ties the four centres together with joint travel grants, courses, and exploitation of infrastructures across the four centres. Future areas of progress will include more shared positions, and thus more collaboration and shared projects; if we are able to launch funding for this as planned. Furthermore, the Partnership has formulated new joint interest areas as a basis for grand challenge projects across two or more centres.
How have translational research studies progressed at NCMM over the last year?
NCMM PIs reported around 50 NCMM-affiliated publications in 2016, and the first quarter of 2017. This includes papers published in Nature Genetics, Oncogene, Current Biology, Journal of Clinical Oncology and many more. Furthermore, there are around 27 clinical trial projects either ongoing or underway, showing that the breadth and depth of research at our centre is continuing to develop and expand.
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AN OVERVIEW FROM THE DIRECTOR
NCMM extramural funding, in the form of grants to the Group Leaders and other competitive funding, has increased steadily from 7 mNOK in 2010 to 42 mNOK in 2015. In 2016, NCMM reached 32 mNOK in extra mural grants. This slight decrease in comparison to previous years is due to some research groups rotating out of the Centre.
How has the Nordic EMBL Partnership benefited NCMM in terms of research collaborations, networking, and infrastructure?
NCMM has been able to enjoy collaborations across the Nordic EMBL Network with all three other nodes, and there has also been a lot of collaboration between NCMM’s own research groups. Speakers from each Nordic EMBL Partnership node have been invited for visits at other nodes, and these visits and networking are something we hope to see more of in the future. We have also been able to make great use of the various outstanding infrastructures offered across the nodes, such as Chemical Biology infrastructures. A separate NordForsk grant has also further helped to facilitate more Chemical Biology collaboration across the nodes.
What are you most looking forward to in the year ahead?
NCMM has a great set of research groups and a lot of very talented staff. I look forward to seeing NCMM groups and individual researchers that have been working hard towards well-defined and ambitious goals for extended periods of time capitalise on all their research efforts. I also look forward to seeing how the most recently recruited groups develop, and what directions they take. Lastly, I look forward also to upcoming recruitments of even newer groups to set up new research in NCMM. It is always an exciting time in a place like NCMM. In a more general context, I am looking forward to the Helsinki NMMN meeting in September, the next NCMM national network meeting in January 2018, and what ambitious goals we can reach for jointly at the Nordic level.
Professor Kjetil TaskĂŠn, NCMM Director
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NCMM history in brief
1 Group Leader hired: Hurtado
3 Group Leaders hired: Nagelhus, Mills and Morth
Appointment of 5 Associate
Appointment of 7 Associate Investigators
EATRIS
2001-2004
2005-2007
2008
EU-OPENSCREEN
Investigators
Taskén appointed Interim Director
Taskén appointed
(2009-2010)
Director (2011-2015)
2009
2010*
2011
Planning &
Financing discussions
Nordic EMBL
Recruitment of first
Official
SAB
Approval process
& negotiations
Partnership Agreement
group leaders
inauguration
established
* PhD course in molecular medicine
NCMM formally
Start of
1st operational
First NCMM
established
operations
year
publications
NCMM Board appointed
BiO • BiO was established in 1989 • After evaluation by UiO in 2002, BiO was reorganised under the EMBL model • In 2003, Kjetil Taskén was appointed as a new Centre Director • Following the reorganisation, BiO was set up as a centre for molecular biology, biotechnology and bioinformatics • The centre had six internationally-recruited research groups, in addition to core facilities.
MERGER BETWEEN NCMM AND BIO
The merger between Centre for Molecular Medicine Norway (NCMM) and the Biotechnology Centre of Oslo (BiO) formally came into effect on 2 January 2017. The new NCMM consists of two departments: NCMM Translational Research (the former NCMM) and NCMM Biotechnology (former BiO). The centre now comprises of 11 Research Groups. Prior to the merger, NCMM and BiO were parallel Centres with a shared model. Both recruited young group leaders to 5+4 year non-tenured positions, and operated with a joint Director.
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Following letters from the European Molecular Biology Laboratory (EMBL), The South-Eastern Norway Regional Health Authority (Helse Sør-Øst), and the Research Council of Norway supporting a merger, the Board of the Faculty of Medicine, on behalf of University of Oslo, decided in June 2016 that BiO and NCMM would merge. The merger of BiO and NCMM will serve to significantly strengthen the Centre scientifically and strategically, alongside reinforcing local anchoring, funding base, and infrastructure. The Centre is still located at Oslo Science Park.
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NCMM HISTORY IN BRIEF
Inaugural NCMM Network Meeting in Oslo
Second Group, Mills, rotates out
1 Group Leader hired: Mathelier
First Group, Nagelhus, rotates out 5 new Associate
Hartmut Luecke
Investigators and 7
2 new Group Leaders,
appointed
1 Group Leader
4th NMMN
New Group Leader
new Young Associate
Gözen and Sekulic,
Assistant Director
hired: Staerk
Meeting in Oslo
Esguerra hired to BiO
Investigators appointed
hired to BiO
(2017-2021)
Taskén re-appointed Director (2016-2020)
2012* 1st SAB visit
2013* 2nd SAB visit
2014* 3rd SAB visit
2015*
2016*
4th SAB visit
2017
5th SAB visit
Rotation of SAB Chair out, new SAB member appointed
Renewal & Expansion of the Nordic EMBL Partnership Agreement (2013-2023)
NCMM 5-year
Funding for 2nd period
NCMM Board re-
Merger decision
Merger between
Evaluation
(2015-19) secured
appointed
NCMM and BiO
BiO and NCMM completed, taking total number of research
SAB re-appointment
NCMM organised under
Norway becomes
UiO Faculty of Medicine
official member
groups to 11
of EATRIS-ERIC, Funding of NOROPENSCREEN as national Norwegian infrastructure
WELCOME TO NEW NCMM ASSISTANT DIRECTOR, HARTMUT LUECKE
NCMM is delighted to welcome Professor Hartmut Luecke as the Centre’s new Assistant Director. Professor Luecke is a structural biologist currently based at the University of California, Irvine, where he is Director of the Centre for Biomembrane Systems and a Professor of Biochemistry. Professor Luecke’s research interests include crystallographic and cryo-EM studies of membrane proteins, with work spanning from discovering how Helicobacter pylori survives at pH 1 in the stomach, to annexins, S100
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proteins, RNA editing, p53, drug discovery, and chemical biology. He will therefore be an excellent addition to the structural biology community in Oslo. Professor Luecke studied for his B.S. at Heidelberg University in Tiffin, Ohio, before obtaining his Ph.D. at Rice University in Houston, Texas. Professor Luecke is expected to start working with NCMM in November 2017, with a full presence at the centre from January 2018.
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RESEARCH GROUPS
NCMM Group Leaders Group Leaders at NCMM should be young, outstanding researchers in an international context. Each has been recruited to non-tenured 5+4 year positions, with a start-up package to set up a research group. These positions are research scientist positions at a level comparable with Associate or Full Professor. THE CURRENT GROUP LEADERS AT NCMM/BIO INCLUDE: NCMM Translational Medicine
Professor Kjetil Taskén, identified by the Research Council as one the founding members of NCMM, served as Interim Director 2008-10. Professor Taskén was appointed Director from January 2011 and reappointed for a second 5-year period from 2016. His research is in the area of cell signalling and immunomodulation, with application in immune diseases, inflammation, and tumour immunology. Dr. Ian G. Mills was recruited from Cambridge Research Institute, Cancer Research UK, University of Cambridge in 2010. Mills is interested in transcriptional and regulatory networks in prostate cancer and aims to better define the interplay between membrane trafficking, metabolism, and transcription in prostate cancer, as proteins in regulatory hubs for these processes have potential value as
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cancer biomarkers and therapeutic targets. Mills accepted a position at Queens University of Belfast in 2015 and rotated out of NCMM in June 2016. Dr. Jens Preben Morth was trained in structural biology at the EMBL Outstation in Hamburg and was recruited from Aarhus University to NCMM in October 2010. His research is in the area of structure and function of membrane transporters. Morth has also started a new programme on pH regulation and structure function studies on bicarbonate transporters. His research has relevance to cardiology, neurobiology, and kidney diseases. Morth’s appointment as group leader was evaluated in 2015 and his position was renewed for a second five-year period (2015-2020). Dr. Toni Hurtado did his PhD at the Vall Hebron Hospital in Barcelona and his postdoc at Cambridge Research Institute, University of Cambridge. Hurtado started as
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NCMM GROUP LEADERS
From left: Anthony Mathelier, Sandra Lopez-Aviles, Nikolina Sekulic, Camila Vincencio Esguerra, Kjetil Taskén, Irep Gözen, Judith Staerk, Jens Preben Morth, Hartmut Luecke, Toni Hurtado
NCMM Biotechnology
Dr. Sandra Lopez-Aviles did her PhD in Barcelona followed by a postdoc in the laboratory of Frank Uhlman at the London Research Institute. She started as Group Leader at BiO in November 2011. Her research is focussed on the role of phosphatases in the yeast cell cycle. Her appointment as group leader was evaluated in autumn 2016 and her position was renewed for a second fiveyear period (2017-2022). Dr. Camila V. Esguerra did her PhD at the University of Leuven, Belgium and was recruited to BiO from the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, where she worked as a senior scientist. Her research is in the area of chemical neuroscience using zebrafish as a model system for epilepsy. Esguerra started as Group Leader at BiO in December 2014. a Group Leader at NCMM in 2011 and his research is focused on breast cancer, estrogen sensitivity, and the role of co-factors in transcriptional networks. Dr. Judith Staerk trained at the Ludwig Institute for Cancer Research and Catholic University in Brussels, did her postdoc at Whitehead Institute, MIT, Boston, US working with stem cells and started in her NCMM Group Leader appointment in 2012. Her research is focused on stem cell biology, hematopoietic stem cells and myelodysplastic and myeloproliferative syndromes. Staerk’s appointment as group leader was evaluated in the autumn of 2016 and her position was renewed for a second five-year period (2017-2022). Dr. Anthony Mathelier is a computer scientist by background who did his PhD at the Pierre and Marie Curie University, Paris. Mathelier was recruited from the University of British Columbia, Vancouver, Canada, which is where he also did his postdoc. Mathelier started his NCMM Group Leader appointment in May 2016. His computational biology research programme focuses on gene expression regulation and the mechanisms by which it can be disrupted in human diseases such as cancer.
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Dr. Nikolina Sekulic did her PhD at the University of Illinois in Chicago, followed by a postdoc in the laboratory of Professor Ben Black at the University of Pennsylvania, Philadelphia. She started as Group Leader at BiO in January 2016 and her research is focussed on structural biology and epigenetics. Dr. Irep Gözen did her PhD in chemical and biological engineering at Chalmers University of Technology in Gothenburg, Sweden followed by a postdoc at HarvardMIT Health Sciences and Technology. She started her group leader appointment at BiO in September 2016 and her research programme will focus on the development and utilization of bionanotechnology-based methods. NCMM has recently also recruited a new senior group leader/assistant director. Professor Hartmut Luecke is a structural biologist, currently based at the University of California (UC), Irvine and will join NCMM in November 2017. Furthermore, NCMM will start the process of recruiting two new group leaders in autumn 2017. The research groups at NCMM are presented in more detail in the following pages.
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RESEARCH GROUPS
Kjetil Taskén
Signalling Networks in Health and Disease A main focus of the Taskén Group is to understand why the immune system sometimes turns off its ability to recognise and kill cells in an expanding malignant tumour. We aim to understand how tumours develop immune evasion strategies, what mechanisms operate in different cancers, and how we can perturb such immune-inhibitory signals to boost anti-tumour immunity and assist other cancer immunotherapies. We are starting work with cancer drug sensitivity screening on patient samples, looking for efficacious compounds and drug synergies on an individual basis, ultimately aiming to assist clinical decisions in precision oncology and haematology. Other activities focus on the role of the cAMP second messenger system and other signal networks in the regulation of cellular function and its involvement in disease mechanisms in inflammation as well as in infectious, metabolic and cardiovascular diseases.
DESCRIPTION OF THE GROUP’S RESEARCH The group aims to understand complex intracellular signalling networks and how such networks require anchoring and localisation through A kinase anchoring proteins (AKAPs) or other scaffold proteins. The group investigates how these signalling networks mediate hormonally regulated physiological and pathophysiological processes. In the immune system we investigate cAMPand regulatory T cell-mediated immune-modulation with application in immune diseases, inflammation and tumour immunology. In pursuit of this understanding the group maps signalling pathways, identifies targets, develops tools to perturb signalling (peptidomimetics, small
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molecular compounds) and provides “proof-of-principle” experiments using specific disease models. The Taskén group employs a breadth of techniques in bioinformatics, proteomics, phospho-flow analysis, chemical biology high-throughput screening assays and genetic tools in order to screen new targets for in vitro and in vivo function. In order to isolate signalling complexes from a variety of targets, including T cells, cardiomyocytes, adipocytes, and organelles such as lipid droplets and mitochondria, a chemical genomics approach is used in combination with phospho-proteomics to understand spatiotemporal dynamics of phosphorylation in anchored signalling complexes. Chemical biology screenings identify small molecular compounds for our research. Furthermore, phospho-flow cytometry using fluorescent cell barcoding allows mapping of complex signal networks, assessing how inhibitory signals feed in and examining how small molecules perturb such signal networks. Our recent technology developments now also allow flow-based signalling analyses of adherent cells and high-throughput chemical biology screening by flow cytometry. The group studies cAMP immunomodulation and involvement of regulatory T cells in HIV, mouse AIDS, and various cancers where tumour immunology is of significance. Projects include studies of regulatory T cells and anti-tumour immune responses in colorectal cancer, pancreatic cancer, cholangiocarcinoma and ovarian carcinoma. In addition, cancer and immune cell signalling analyses are being performed by phospho-flow cytometry to find bio signatures. A recent interest is now to rig drug sensitivity screens to explore the possibility to assist treatment choices in individualised
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RESEARCH GROUPS: KJETIL TASKÉN cancer therapy, particularly looking at haematological malignancies. Furthermore, systems biology analyses are applied on the phospho-flow data from single cell signalling as well as from mixed cell populations with Treg immunosuppression. The improved understanding of signalling networks can be applied to many disease states, including immune-deficiencies, inflammatory disorders and cancers and may promote the development of highly specific pharmaceuticals that maximise their therapeutic value, while minimising unwanted side-effects.
ACHIEVEMENTS IN 2016 • Professor Kjetil Taskén awarded the King Olav V’s Prize for Cancer Research 2016, for his work with immunotherapy. • Paper in Journal of Clinical Oncology by Simer Bains et al attracted significant media attention, with over 100 press items generated.
Key Publications from the Taskén Group:
20+ papers were published in 2016/Q1 2017, including co-authored papers in Cell Reports and Leukaemia, both with an impact factor of around 10. Other highlights include the Group’s first paper on the CLL / cancer drug sensitivity screening (Parente-Ribes, Skånland et al) and a paper in the Journal of Leukocyte Biology (Chelappa et al) where the journal wrote an Editorial on our paper: Parente-Ribes, A.*, Skånland, S.S.*, Bürgler, S.*, Os, A, Wang, D., Bogen, B., Tjønnfjord, G.E., Taskén, K.$,#, Munthe, L.A. $,# (2016) Spleen tyrosine kinase inhibitors block CD40L induced proliferation of chronic lymphocytic leukaemia cells. Haematologica, 101:e59-62. Chelappa, S., Lieske, N.V., Hagness, M., Line, P.D., Taskén, K.,#Aandahl, E.M.# (2016) Human regulatory T cells control TCR signalling and susceptibility to suppression in CD4+ T cells. J. Leukocyte Biol., 100:5-16. (#corresponding authors) - In section “Spotlight on Leading Edge Research”, Editorial: Jeschke & Williams. Treg potency and the importance of being fit. Ibid, 1-3. Professor Kjetil Taskén was senior author on a report examining digital technology and its potential for facilitating faster research and development, and generating value within Norway’s biology economy. The report, Digital Biology in Norway – Opportunities for Creating Value, Skills Needs, and Challenges in Economic Development, was published by Centre Digital Life Norway in March 2017.
Summary of grants awarded 2016/Q1 2017:
• Awarded a Cancer Society programme grant for 2017-2020 for the Taskén Group (6m NOK)
• •
Won a Helse Sør-Øst (Regional Health Authority for South-Eastern Norway) programme grant for 2017-2019 (4.5m NOK) Co-PI on a Cancer Society programme grant to fund our clinical trial on ASA intervention in colorectal cancer (6m NOK) 2017-2020 • Co-PI on a KLINBEFORSK (Department of Health and Social Services) grant to fund Group’s clinical trial on ASA intervention in colorectal cancer (19m NOK) 2017-2021 • Awarded UiO Innovation grant for 2017-2018 (800k NOK)
PhD defences from the Taskén Group in 2016: • • • •
Simer J. Bains Stalin Chelappa Nora V. Lieske Alexandra Dukic
Some 20+ talks were held nationally and internationally including:
• Research Council of Norway, Industry Day, April 19, 2016 in Det Norske Teatret. Speaker: Gene technology moves boundaries in medicine. • 43rd Scandinavian Society for Immunology meeting, Turku, Finland, 2016 • 19th Annual Broegelmann Lecture, University of Bergen, 2016 • Int. Congress of Immunology, Melbourne, Australia, 2016 • Fifth International Meeting on Anchored cAMP-signalling pathways, Zermatt, Switzerland, 2016 • Norwegian Society for Oncology Annual Meeting, Trondheim, 2016 • Oslo Life Science Conference 2017, February 6, speaker. • Kobe University Symposium, Kobe Japan, March 14, 2017. Invited Speaker. (This was tri-university collaboration meeting – We have signed a MOU with Kobe and U Washington in Seattle).
FUNDING In addition to support from NCMM and the Biotechnology Centre of Oslo, the Taskén Group has, in 2016, received support from: • • • • • • • • •
University of Oslo – Digital Life funding The Research Council of Norway – including Biotek2021, NOR-OPENSCREEN The Norwegian Cancer Society Helse Sør-Øst Norwegian Department of Health and Social Services European Commission – including EATRIS, EU-Openscreen Novo Nordisk Foundation Jebsen Centre for Cancer Immunotherapy Jebsen Inflammation Research Centre
*,$ equal contributions, #corresponding authors
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RESEARCH GROUPS: KJETIL TASKÉN
GROUP MEMBERS
COLLABORATIONS
Research Scientists
International collaborations
Einar Martin Aandahl Johannes Landskron Sigrid Skånland
Postdoctoral Fellows
Theresa Ahrens (joint with Staerk group) Simer Jit Bains (NCMM, affiliate) Deepak Balaji Thimiri Govinda Raj Ana I. Costa Calejo Stalin Chelappa (from July 2016) Dinh-Toi Chu Andrea Cremaschi (from October 2016) Aleksandra Dukic (from January 2017) Kushi Kushekhar Anna-Mari Lone Kristina B. Lorvik Vanessa L Wehbi (until January 2017) Nn, open postdoc (Cancer Society grant, 2017- hiring ongoing) Nn, open postdoc (Helse Sør-Øst grant, 2017- hiring ongoing) Nn, open postdoc (KG Jebsen Centre grant, 2017- hiring ongoing)
PhD. Fellows
Stalin Chelappa (until June 2016) Aleksandra Dukic (until December 2016) Nora V. Lieske (until June 2016) Ellen Østensen
MSc/MD Students
Johanne Hermansen Uthus Marthe Jøntvedt Jørgensen
Administrative Officer Berit Barkley
Scientific Officers Marianne Enger Martine Schrøder Gladys Tjørhom
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We currently collaborate with the groups of Professor John D. Scott, University of Washington, Seattle; Professor Friedrich Herberg, Universität Kassel; Professor Sven Enerbäck, Göteborgs Universitet; Professor Manuela Zaccolo, University of Oxford; Dr. Enno Klussmann, Max Delbrück Centre for Molecular Medicine, Berlin; Professor Riitta Lahesmaa, University of Turku; Professor Albert Heck, The Netherlands Proteomics Centre, Utrecht; Dr. Joe Lewis, Chemical Biology Unit, EMBL; Group leader Klaus Okkenhaug, Babraham Institute, Cambridge, UK; Dr. Guillaume Pidoux, Université Paris Süd; Professor Bodo Grimbacher, Freiburg University; Dr. Julio SaezRodrigues, EMBL-EBI, Hinxton / Univ of Aachen, UK; Professor Mikael Elofsson, MIMS, Umeå, Sweden, Dr. Krister Wennerberg, FIMM, Helsinki, Finland, Professor Tobias Bopp, University of Mainz and others.
National collaborations
The group collaborates with Group Leaders Judith Staerk, J. Preben, Morth and Camila Esguerra Biotechnology Centre / NCMM and Professors Heidi Kiil Blomhoff, Philippe Collas, Jo Klaveness, Arnoldo Frigessi, Bernd Thiede, University of Oslo; Professors Dag Kvale and Anne Ma Dyrhol-Riise, Dept. of Infectious Diseases, Senior Consultants Bjørn Atle Bjørnbeth and Sheraz Yaqub, Gastrosurgical Dept., Professor Ivar Sjaastad, Institute of Experimental Medical Research, Professor Guttorm Haraldsen, Dept. of Pathology, Professor Ludvig Munthe, Institute of Immunology, Professor Geir E. Tjønnfjord, Senior Consultants Ingunn Dybedahl and Fredrik Schjesvold, Dept. of Haematology, Professor Pål Aukrust Dr. Arne Yndestad, Professor Bente Halvorsen and Professor Tom Hemming Karlsen; Inst. of Internal Medicine Research, Professors Johanna Olweus and Kalle Malmberg, Dept of Immunology, Inst. for Cancer Res., Senior Consultant Jon Amund Kyte, Dept. of Oncology, and Professor Annetine Staff, Dept Ob-Gyn, Sen. Consultants Are Holm and Karl Otto Larsen, Dept of Lung Diseases, Oslo University Hospital; Professor James B. Lorens, University of Bergen, Professor Bjørn Tore Gjertsen, Senior Consultant Line Bjørge, Haukeland University Hospital, Bergen; Professor Anders Sundan, NTNU, Senior Researcher Geir Klinkenberg, SINTEF, Rafi Ahmad, Hedemark Univ. College and others.
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RESEARCH GROUPS
Ian G. Mills
Prostate Cancer Research Group Prostate cancer is a high-incidence cancer in men with progression to metastatic disease occurring in around 20-30% of detected cases. Major translational challenges include the development of biomarkers able to predict progression at the time of diagnosis and treatment response/failure as well the need to develop more effective treatment strategies. Our strategy for addressing this has been to explore how transcription factors and chromatin change in transformed cells and how the gene networks that they regulate map back to clinical expression profiles. From the resultant gene networks and pathway enrichments we have identified biological processes that we believe are important to regulate progression and treatment response and have gone on to study these functionally and, with clinical collaborators, to evaluate candidate biomarkers. From this work the main biological focus of the group is on stress response signalling, sub-divided broadly into glycosylation and the unfolded protein response/autophagy. In particular, we are focussing on how genes that function in these processes confer resistance to therapeutic and oncogenic stress and how they can be targeted therapeutically.
DESCRIPTION OF THE GROUP’S RESEARCH Chromatin biology and transcriptional regulation:
Predominantly we employ high-throughput sequencing and transcript profiling to map genome-wide changes in transcription factor recruitment and chromatin compaction in cell-lines and clinical samples. By using these approaches we have found that chromatin opening is a hallmark of lethal castrate-resistant disease and that the activity of a key transcription factor in prostate cancer, the androgen receptor (AR), is modified by the expression of other oncogenic transcription factors with a focus here principally on c-Myc. Additionally, we have found
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that regions of open chromatin are hotspots for prostate cancer risk loci.
Autophagy:
Autophagy (‘self-eating’) is a key stress response that can have pro-survival or pro-apoptotic properties in cancer cells depending on the context and trigger. Whilst this has been recognised by groups worldwide, the desire to achieve clinical translational endpoints through the study of autophagy has led to the over-interpretation of assays and autophagic markers. A key contribution that we are making in this area is to carefully dissect whether autophagic markers are also necessary to drive the functional biology of the autophagic process. We are addressing this by developing and qualifying autophagic assays and then testing the impact of genetic targeting of autophagic factors. With that knowledge in place the programme will then move on to explore how these factors affect response to treatments such as anti-androgens.
Glycosylation:
Glycosylation is a bridge between metabolic changes, protein folding capacity and in turn the stability and activity of oncogenes. We realised the potential importance of glycosylation early in the development of our research program based on clinical profiling and mapping of target genes for the androgen receptor and other transcription factors. In particular, we have been exploring how a pathway called the hexosamine biosynthesis pathway affects the stability of c-Myc and other oncogenes and the response to activators of the unfolded protein response. This pathway is fuelled by metabolites drawn from all of the core metabolic processes in the cell to form a single amino-sugar-nucleotide conjugate – UDP-GlcNAc. Whilst heightened activity of this pathway is required to sustain protein folding in untransformed secretory cells, the same pathway can also confer resistance to environmen-
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RESEARCH GROUPS: IAN G. MILLS
tal stress and consequently the expression and activity of enzymes in the pathway and fuelled by the pathway are retained and amplified in cancer cells.
Biomarkers:
Since prostate cancer progresses in a subset of diagnosed cases to a lethal metastatic disease and the current biomarker, prostate specific-antigen (PSA), is relatively ubiquitous, there is a significant need for biomarkers that flag heightened risk of disease progression. We are evaluating transcripts and proteins as candidate biomarkers, focussing predominantly on ‘liquid biopsy’ (urine, blood and circulating tumour cells). Amongst these sample types we have so far made most progress in evaluating markers in blood samples. Since it typically takes 5-10 years from diagnosis to disease progression, blood samples represent a sample type that currently has the longest follow-up time having been biobanked. By contrast, urine sample collections are still relatively recent and there remains controversy over the best detection platform for circulating tumour cells. The biomarkers that we have been testing have arisen from three sources. Transcript biomarkers have either been derived from our pre-clinical studies or through collaboration with international research consortia. Protein biomarkers have arisen from proteomic profiling of Janus Serum Bank samples and downstream validation in samples obtained from other Nordic and UK sample collections through collaboration.
ACHIEVEMENTS IN 2016/Q1 2017 • Professor Per Seglen (Guest Researcher) – will be awarded the King Olav V’s Prize for Cancer Research 2017 in June, in recognition of his seminal work on autophagy • Lisa Gerner (PhD student) – successfully defended her thesis in Q1 2017 • Bertrand Simon (PhD student – co-supervised by Ian Mills but based at EMBL Hamburg) – successfully defended his thesis in Q1 2017
FUNDING In addition to support from NCMM, the Mills Group has, in 2016, received additional support from: • The Research Council of Norway – Young Talent Award to Nikolai Engedal, and FIRMEDBIO • Helse Sør-Øst – three-year postdoc position for Dr. Alfonso Urbanucci • Movember/Cancer Society Team Science Award • The Norwegian Cancer Society – Funding for three years, for two postdocs
GROUP MEMBERS Head Engineers
Ingrid Jenny Guldvik (until June 2016) Frank Sætre (until July 2016)
Senior Researcher Nikolai H. Engedal
Guest Researcher Per O. Seglen
Postdoctoral Fellows Harri Itkonen Alfonso Urbanucci
PhD Fellows
Lisa Gerner (until February 2017) Morten Luhr Bertrand Simon – Joint PhD student at EMBL Hamburg (until March 2017) Paula Szalai
Publications from Mills Group 2016/Q1 2017
Some 20+ publications were published in 2016/Q1 2017, including co-authored papers in high impact factor journals, such as Nature Genetics, Journal of the National Cancer Institute, European Urology, Autophagy, and many more.
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RESEARCH GROUPS: IAN G. MILLS
COLLABORATIONS Thorsten Schlomm, Eppendorff Hospital, Hamburg, Germany (Biomarkers) Henrik Gronberg/Fredrik Wiklund, Karolinska Institute, Sweden (Biomarkers) David Neal, Cambridge University, UK (Biomarkers) Kristin A. Taskén, OUS/UiO (Biomarkers) Ole Andreassen, OUS/UiO (Genetic risk) Fahri Saatcioglu, OUS/UiO (Stress response signalling) Preben Morth, NCMM (Calcium/calmodulin-dependent kinases in cancer) Judith Staerk, NCMM (Epigenetics in haematological malignancies) Toni Hurtado, NCMM (Transcriptional regulation in hormone-dependent cancers) Ole Petter Rekvig, University of Tromsø, Norway (Lupus markers and biology in cancer) Wolfgang Lilleby, OUS (Biomarkers) Suzanne Walker, Harvard University, Massachusetts, USA (OGlcNAc Transferase) Angelo DeMarzo, John Hopkins University, Maryland, USA (c-Myc)
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Paul Rennie/Ladan Fazli, Prostate Cancer Centre, Vancouver, Canada (Signalling and biomarkers in prostate cancer) Matthias Wilmanns, EMBL Hamburg, Germany (Calcium/calmodulin-dependent kinases in cancer) Tapio Visakorpi, University of Tampere, Finland (Chromatin biology and androgen receptor signalling in prostate cancer/biomarkers) Andrei Chabes, MiMS/University of Umeå, Sweden (Nucleotide biosynthesis) Yvonne Ceder, Lund University, Sweden (Non-coding RNA in prostate cancer) Anne Simonsen, UiO (Autophagy) Maria Theresa Landi, National Cancer Institute, Maryland, USA (Genetic risk – lung cancer) Olli Kallioniemi/Paivi Ostling, SciLife Lab/Karolinska Institute, Sweden (Screening to identify sensitisers to anti-androgens) Poul Nissen, DANDRITE/Aarhus University, Denmark (SERCA inhibition and autophagy) Lorena Arranz, University of Tromsø, Norway (Transcriptional regulation in haematological malignancies)
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RESEARCH GROUPS
J. Preben Morth
Membrane Transport Group The Morth group employs a structural systems biology approach to investigate the proteins involved in acidbase homeostasis and metal ion transport across the cellular membrane. A variety of techniques are used in order to identify and characterise both soluble and membrane bound proteins involved in pH regulation. A bioinformatics approach is used to target new proteins and interaction partners of interest. Furthermore, X-ray crystallography and several biophysical methods to obtain structural information as well as biochemical techniques are also used, including activity assays and fluorescence spectroscopic measurements.
DESCRIPTION OF THE GROUP’S RESEARCH To study the 3D atomic structure of membrane proteins, the group is currently developing purification and lipid vesicle reconstitution protocols. The aim is to purify and characterise these membrane proteins.
The bicarbonate transporters
Acid-base homeostasis is fundamental to our understanding of human physiology and is essential to cellular function. The main buffering system found in the human body is based on bicarbonate. The SLC4 proteins are the main facilitators of bicarbonate transport across the plasma membrane, however, not much is known about the structural basis of function and regulation of these. The N-terminal cytoplasmic domain (NTD) of the sodium-coupled chloride bicarbonate exchanger (NCBE), found predominantly in the choroid plexus of the brain, has been cloned, expressed and purified. The core domain found centrally in the NTD has been crystallized and the structure determined at 4.0 Ă… resolution. The NTD of NCBE is found to contain regions of intrinsic protein disorder and these disordered regions are conserved among all bicarbonate transporters of the SLC4 family. The disordered regions coincide with regions of sequence variation, indicating that although sequence is not conserved, the disorder is.
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P-type ATPases in infectious diseases
The system is strongly dependent on the ion gradients maintained by the P-type ATPases. The group therefore aims to develop a complete structural model for anion transport and recognition. Structural analysis of P-type ATPases will continue with focus on the prokaryotic Ca2+ ATPases and Mg2+ ATPases. In particular, we are focusing on their function as participants in virulence systems. The systems in question originate from Listeria monocytogenes and Salmonella typhimurium, and our work on translation in infectious diseases like Salmonella will bridge the gap between lab bench and clinic. Our strong focus on developing in vitro assays to study these particular membrane transporters will allow direct inclusion into the exciting drug screening platforms in Europe. Furthermore, these projects can benefit the broad scientific community located in Oslo, focusing on infectious diseases.
Characterisation of supramolecular Tankyrase complexes implicated in colorectal cancer, using an intrinsically disordered protein as bait.
A translational project focusing on identification of large supramolecular complexes implicated in the Wnt pathway was initiated by the Morth group. We are performing structural studies of a human ADPribosyltransferase tankyrase (TNKS), trying to identify novel direct interaction partners by using a proteomics approach in collaboration with Bernd Thiede (UiO). Tankyrases belong to the poly (ADP-ribose) polymerase (PARP) superfamily and are involved in various cellular functions such as telomere maintenance, centrosome maturation, Wnt signalling, embryonic development and the pathogenesis of Cherubism. We are currently aiming to isolate and characterise proteins that bind to the full length tankyrase enzyme, a protein of more than 1200 residues and with several potential and verified interaction partners. We are therefore combining our structural and biochemical studies with cellular assays, using the strong imaging platforms built up by Oddmund Bakke (UiO).
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RESEARCH GROUPS: J. PREBEN MORTH ACHIEVEMENTS IN 2016
FUNDING
Publications from the group:
In addition to support from NCMM, Morth Group has, in 2016, received additional support from:
Bauer J, Bakke O, Morth JP. Overview of the membrane-associated RING-CH (MARCH) E3 ligase family. N Biotechnol. 2016 Dec 14. pii: S1871-6784(16)32629-2. doi: 10.1016/j.nbt.2016.12.002. [Epub ahead of print] PubMed PMID: 27988304. Gerner L, Munack S, Temmerman K, Lawrence-Dörner AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG, Morth JP. Data for the co-expression and purification of human recombinant CaMKK2 in complex with calmodulin in Escherichia coli. Data Brief. 2016 Jun 29; 8:733-40. doi:10.1016/j.dib.2016.06.033. eCollection 2016 Sep. PubMed PMID: 27508226; PubMed Central PMCID: PMC4950174. Bjerregaard-Andersen K, Østensen E, Scott JD, Taskén K, Morth JP. Malonate in the nucleotide-binding site traps human AKAP18γ/δ in a novel conformational state. Acta Crystallogr F Struct Biol Commun. 2016 Aug; 72(Pt 8):591-7. doi:10.1107/S2053230X16010189. Epub 2016 Jul 13. PubMed PMID: 27487922; PubMed Central PMCID: PMC4973299. Leo JC, Oberhettinger P, Yoshimoto S, Udatha DB, Morth JP, Schütz M, Hori K, Linke D. Secretion of the Intimin Passenger Domain Is Driven by Protein Folding. J Biol Chem. 2016 Sep 16; 291(38):20096-112. doi: 10.1074/ jbc.M116.731497. Epub 2016 Jul 27. PubMed PMID: 27466361; PubMed Central PMCID: PMC5025694. Hong Z, De Meulemeester L, Jacobi A, Pedersen JS, Morth JP, Andreasen PA, Jensen JK. Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1: FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZTYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN. J Biol Chem. 2016 Jul 1; 291(27):14340-55. doi: 10.1074/ jbc.M115.707240. Epub 2016 May 6. PubMed PMID: 27189939; PubMed Central PMCID: PMC4933187.
• The Norwegian Cancer Society • The Research Council of Norway • Marie Curie • NordForsk
GROUP MEMBERS Principal Engineer Bojana Sredic
Postdoctoral Fellows
Johannes Bauer Harmonie Perdreau-Dahl Saranya Subramani
PhD Fellow
Julia Weikum (from April 2017)
Students
Annika Kratzel, Erasmus Student (April - July 2017) Maria Wahle (May - September 2017)
COLLABORATIONS Oddmund Bakke, Department of Biosciences, UiO Sandip Kanse, Institute of Basic Medical Sciences, UiO Maria Eugenia Chollet Dugarte, Oslo University Hospital Grethe Skretting, Oslo University Hospital Maria Skepo, Lund University, Sweden Lise Arleth, Copenhagen University, Denmark Michael Palmgren, Copenhagen University, Denmark Kresten Lindorff-Larsen, Copenhagen University, Denmark Michele Cascella, Department of Chemistry, UiO William Louch, Oslo University Hospital (Ullevål)
Gerner L, Munack S, Temmerman K, Lawrence-Dörner AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG, Morth JP. Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2. Biochem Biophys Res Commun. 2016 Jul 22; 476(2):102-7. doi: 10.1016/j.bbrc.2016.05.045. Epub 2016 May 11. PubMed PMID: 27178209. Subramani S, Perdreau-Dahl H, Morth JP. The magnesium transporter A is activated by cardiolipin and is highly sensitive to free magnesium in vitro. Elife. 2016 Jan 18; 5. pii: e11407. doi: 10.7554/eLife.11407. PubMed PMID: 26780187; PubMed Central PMCID: PMC4758953.
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RESEARCH GROUPS
Antoni Hurtado
Breast Cancer Group The main interest of the group is to understand the mechanism of hormone resistance in breast cancer. Moreover, we are interested in determining how the estrogen antagonist Tamoxifen contributes to the inhibition of breast cancer progression. Therefore, the focus of my future research is summarised in two main projects: (1) Elucidating the role of cell-signalling pathways controlling FOXA1 functions in Breast Cancer (2) Searching for novel mechanisms of action for the anti-ER drug Tamoxifen.
DESCRIPTION OF THE GROUP’S RESEARCH Elucidating the role of cell-signalling pathways controlling FOXA1 functions in Breast Cancer Resistance to endocrine therapy is complex, heterogeneous and may differ from patient to patient. The majority of clinical trials thus far have focused on combining or alternating endocrine therapy agents, or intercalating targeted therapies against kinase inhibitors such as CDK, PI3KAKT-mTOR, EGFR or HER2. However, cancer cells can eventually find other means to proliferate, and therefore escape the arrest imposed by these treatments. For instance, treatment with AKT inhibitors has been shown to induce activation of SGK1, which continues to support cell proliferation (Castel, Cancer Cell 2016). Having seen that FOXA1 was an important mediator of HER2/HER3 signalling (Gilfillan, Nat Communication in resubmission), we decided to study how other pathways with implications in cell proliferation could regulate its function. Our final goal is to better understand the mechanisms that lead to resistance to current treatments and that are mediated by FOXA1. To test whether other kinases impact FOXA1 function, we have carried out a drug screening using a selected subset of kinases and phosphatases with known implications in breast cancer,
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and analysing their effect on FOXA1 activity. Subsequently, we performed the chemical screening in hormone-sensitive and hormone-resistant cell lines, which were positive for the expression of FOXA1. We identified 23 potential kinases targeting FOXA1. Next, we repeated the drug screening with 45 inhibitors targeting these kinases. As a proof of principle, with this system we could confirm our previous results regarding the regulation of FOXA1 by the HER2 pathway. Taken together, our preliminary results show that our reporter system is appropriate as a first approach to investigate FOXA1 function and also suggest that FOXA1 mediates the signals of these kinases in the control of proliferation for hormone-resistant patients.
Searching for novel mechanisms of action for the antiER drug Tamoxifen To date, the precise mechanism of action of Tamoxifen is not completely understood, mainly due to the fact that the current studies on the molecular characterisation of tamoxifen action are based on the idea that those compounds target exclusively ER (Shang, Cell 2000). However, the more we understand about the molecular mechanisms of other drugs targeting other proteins, the more we realize that they are generally promiscuous with regard to their biological targets and effects. Hitting multiple targets can enable a drug to be applied therapeutically in several potentially unrelated diseases; or, if more than one of the drug’s targets is involved in pathways relevant to a particular disease, the drug may have increased efficacy for this therapeutic application. For instance, the anti-ER drugs Tamoxifen and Fulvestrant increase Bcl-2 levels and inhibit growth of breast carcinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independently of ER (Long, JBC 2006).
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RESEARCH GROUPS: ANTONI HURTADO
In this study, we aimed to identify targets relevant for Tamoxifen repressive action. We used a chemical proteomics approach, which allows the identification of drug targets. Next, we performed proteomics to identify novel Tamoxifen-interacting proteins and compared to protein targets of ER-tamoxifen. Importantly, this targeted proteomics approach revealed that 50% of the Tamoxifenbiotin pulled down proteins were also identified within the ER-Tamoxifen pull down, which confirmed the suitability of this method to identify Tamoxifen-interacting proteins. In addition, we have also identified other proteins not present within the list of ER-interacting proteins. Tamoxifenassociated proteins identified at least in two replicates and excluded from the negative control (biotin beads) were considered as positive hits. Among these Tamoxifen ER-independent targets we have identified the protein SKIP, which is an important modulator of TGF-beta/Smad signalling. Previously, it has been reported that ER and TGFbeta signalling have opposite roles in proliferation and apoptosis. Whereas ER induces a transcriptional program that triggers proliferation and inhibits apoptosis, TGF-beta induces cell growth arrest and promotes apoptosis (Band, Mammary Gland Biology Neoplasia 2011). Moreover, their regulatory pathways intersect, and ER blocks TGF-beta pathway by multiple means, including direct interactions of its signalling components Smads (Band, Mammary Gland Biology Neoplasia 2011). Considering the intricate roles of these major signalling pathways in mammary epithelial cells biology and tumorigenesis, and their extensive interactions, we are currently investigating how Tamoxifen regulates the crosstalk between these pathways.
ACHIEVEMENTS IN 2016 • Paper published in Nucleic Acids Research (NAR) by Elisa Fiorito (PMID: 27638884); Hurtado lead author • The manuscript ‘Breast tumours escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/3 and deacetylated FOXA1’ by Gilfillan et al is re-submitted to Nat Communications • The manuscript ‘DNA methylation at enhancers distinguishes distinct breast cancer lineages’ by Fleischer et al is re-submitted to Nat Communications • The manuscript ‘FOXA1 predicts good outcome in HER2+ endometrial cancer patients by inhibiting EGFR/HER2 signalling’ by Gilfillan et al is re-submitted to Journal of the National Cancer Institute.
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FUNDING In addition to support from NCMM, the Hurtado Group has, in 2016, received additional support from: • The Norwegian Cancer Society • EU FP7-PEOPLE-2013 COFUND - Sciencia Fellow programme • Research Council of Norway - Frimedbio Young Talent programme • Helse Sør-Øst (HSØ) - Open Project
GROUP MEMBERS Head Engineer Siv Gilfillan
Postdoctoral Fellows
Anne Marthe Fosdahl Sachin Kumar Singh (from September 2016) Venkata Sateesh Somistetty (until January 2017)
PhD Fellow
Shixiong Wang
MSc Student
Neus Daviu (Erasmus student, September 2016-April 2017)
COLLABORATIONS Dr. Therese Sørlie, Oslo University Hospital Prof. Camilla Krakstad, University of Bergen and Haukeland University Hospital, Bergen, Norway Prof. Vessela Kristensen, Oslo University Hospital Dr. Preben Morth, NCMM Dr. Minna U. Kaikkonen, University of Eastern Finland Dr. Meritxell Bellet, Vall-Hebron Research Institute, Barcelona, Spain Dr. Jason Carroll, CRI-CRUK, Cambridge, UK Dr. Maurizio Scaltriti, Memorial Sloan Kettering Cancer Center, NY, USA
C E N T R E FO R M O L E C U L A R M E D I C I N E N O R WAY | A N N UA L R E P OR T 2016
RESEARCH GROUPS
Judith Staerk
Stem Cell Group The Staerk Group focuses on deciphering molecular processes that govern hematopoietic specification, hematopoietic stem cell (HSC) renewal and differentiation as well as formation of mature blood cells. Understanding the mechanisms governing blood development is needed to decipher the underlying molecular events that drive lifelong formation of blood cells, and to identify pathways that are dysregulated in blood disorders. The overall goals of the group’s research are to: i) functionally characterise epigenetic and genetic factors and signalling pathways during hematopoietic development, ii) decipher the mechanism by which the nuclear lamina modulates hematopoietic development, and iii) identify underlying molecular causes of myeloid blood disorders triggered by defects in lineage differentiation that the group studies in the physiologic setting. To achieve these goals, the group is using human pluripotent stem cells, in vitro differentiation assays, as well as animal models along with primary patient samples. The group combines these assays with genetic and genomic approaches.
DESCRIPTION OF THE GROUP’S RESEARCH Epigenetic dynamics during blood cell differentiation
One focus of the group is to understand how epigenetic signatures influence cell fate determination during mesoderm and hematopoietic cell specification. DNA methylation is an epigenetic modification, which is key to numerous processes, including regulation of gene expression and maintaining genomic integrity. Additional complexity to the overall gene regulation has been added by the discovery of Ten-ElevenTranslocation (TET) enzymes, which are dioxygenases that catalyse the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The group characterised 5hmC distribution in CD34+ cells, and mature blood lineage cells. Our results showed that in CD34+
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cells, 5hmC primes expression of genes regulating myeloid and lymphoid lineage commitment. Moreover, in CD34+ cells, 5hmC at enhancers was associated with increased binding of RUNX1 and FLI1 that are TFs crucial for haematopoiesis. To further investigate the role of 5hmC during human blood cell differentiation, the group established oxBS-seq and deleted endogenous TET2 and/or TET3 in hESC lines that encode reporter genes to monitor blood cell differentiation.
Projects with translational impact
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterised by impaired haematopoiesis and a predisposition to developing acute myeloid leukaemia (AML). The underlying cause for MDS is incompletely understood. The group is using primary patient samples as well as patient-derived induced pluripotent stem cells to analyse the potential of these iPSC to differentiate into hematopoietic progenitors, and to screen transcription factor and miRNA libraries to identify candidate genes to reverse the potential block in in vitro blood cell differentiation. Chronic lymphocytic leukemia (CLL) is a common hematological cancer in adults and is characterised by clonal B cell expansion. In the past year, the group assessed cell cycle defects in CLL, and found that a significant number of CD19+ B cells isolated from peripheral blood CLL samples are arrested in cytokinesis. The group linked the observed cytokinesis arrest to reduced NuMA and p53 protein levels, and showed that proteins known to be crucial for cell division, checkpoint and centromere function were dysregulated.
Lamin proteins and haematopoiesis
More recently, the Staerk group has developed an interest in the nuclear lamina (NL)/lamin proteins. Lamins are divided into A-type lamins that are expressed in most somatic cell types, but are not expressed in stem cells,
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while B-type lamins (LMNB1 and LMNB2) are highly expressed in both, stem cells and differentiated cell types. Apart from the well-established role in forming a scaffold underneath the inner nuclear membrane, the NL has been implicated in nuclear positioning of chromatin and transcriptional regulation, which is thought to be critical for cell fate decisions. Moreover, recent studies show that a mutation in lamin A/C (LMNA) leads to altered distribution of histone H3 lysine 27 trimethylation (H3K27me3) in fibroblasts, implicating the interplay between the NL, the epigenetic landscape and probably also direct interaction with epigenetic enzymes. When the process of characterising changes of NL components more closely was started, the group was surprised to find very few studies addressing lamin protein function in blood cells. The group uses ChIP-Seq analysis and generated human ESC that are deficient or overexpress components of the NL to more closely assess how lamin proteins affect human blood development.
ACHIEVEMENTS IN 2016 Publications
Tekpli X, Urbanucci A, Hashim A, Vågbø CB, Lyle R, Kringen MK, Staff AC, Dybedal I, Mills IG, Klungland A, Staerk J. Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells. 2016. Epigenetics Chromatin. May 31; 9:21.PMID: 27252783
PHOTO: JO MICHAEL
RESEARCH GROUPS: JUDITH STAERK
GROUP MEMBERS Principal Engineer Kirsti E. Præsteng
Postdoctoral Fellows Theresa Ahrens Safak Caglayan Artur Cieslar-Pobuda Adnan Hashim Marie Rogne
PhD Fellows
Julia Madsen-Østerbye Oksana Svärd
COLLABORATIONS Stefan N Constantinescu, Ludwig Institute for Cancer Research, Brussels, Belgium Petr Bartunek, Institute of Molecular Genetics, Prague, Czech Republic Karl-Johan Malmberg, OUS/UiO Geir Tjønnford, OUS Ingunn Dybedal, OUS
FUNDING In addition to support from NCMM, the Staerk Group has, in 2016, received additional support from: • The Cancer Society • The Research Council of Norway – Stem Cell Programme and Young Talent Grant • University of Oslo • FP7-CoFund
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RESEARCH GROUPS
Anthony Mathelier
Computational Biology and Gene Regulation The Mathelier Group develops and assesses computational methods to analyse genomic sequences (DNA). The goal of the group is to create the next generation of cutting-edge algorithms and open computational biology software, with immediate application to real-life biological problems.
DESCRIPTION OF THE GROUP’S RESEARCH The group’s computational biology research program aims at furthering the understanding of gene expression regulation (when and where genes are expressed), and the mechanisms by which it can be disrupted in human diseases such as cancer. Thanks to high-throughput sequencing technologies, the group has unprecedented opportunities to study the human genome in the context of diseases. While most studies have focused on genomic regions encoding for proteins (and representing only ~2% of the human genome), the group tries to predict which mutations in cis-regulatory DNA regions (switches to regulate when and where genes are transcribed from DNA to RNA) are causal for diseases.
mutations within TF binding sites can alter gene expression, triggering human diseases such as cancer. As successful computational biology research relies on high quality data for which the group has a strong understanding, work is currently focused on combining large amounts of experimental data with in house computational models to identify the binding sites of TFs. This work will provide the group with a critical map of where TFs bind in the human genome for further studies. The group next plans to combine whole genome sequencing and gene expression data from cancer patient samples with its high-quality regulatory map. This will provide new insights into the predictions of the impact of the mutations dysregulating gene expression and contributing to cancer.
Transcription factors (TFs) are key proteins binding to these switches to control when, where, and to what extent genes are transcribed. It has been shown that
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RESEARCH GROUPS: ANTHONY MATHELIER
ACHIEVEMENTS IN 2016
FUNDING
Lab started in May 2016; early hires include a PhD student and a Postdoctoral Fellow.
Support received from NCMM
Publications
GROUP MEMBERS
• A. Khan and A. Mathelier. Intervene: a tool for intersection and visualization of multiple gene or genomic region sets. bioRxiv, 2017. https://doi.org/10.1101/109728 • C.-H. Lecellier, W.W. Wasserman, R. Rohs, and A. Mathelier. Human enhancers associated with immune response harbour specific sequence composition, activity, and genome organization. bioRxiv, 2016. https://doi.org/10.1101/078477 • M. Lizio, J. Harshbarger, I. Abugessaisa, S. Noguchi, A. Kondo, J. Severin, C. Mungall, D. Arenillas, A. Mathelier, Y.A. Medvedeva, A. Lennartsson, F. Drabløs, J.A. Ramilowski, O. Rackham, J. Gough, R. Andersson, A. Sandelin, H. Ienasescu, H. Ono, H. Bono, Y. Hayashizaki, P. Carninci, A.R.R. Forrest, T. Kasukawa* and H. Kawaji*. Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals. Nucleic Acids Research, 2016. doi: 10.1093/nar/gkw995 • A. Mathelier, B. Xin, T.-P. Chiu, L. Yang, R. Rohs, and W.W. Wasserman. DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo. Cell Systems, 2016. doi:10.1016/j.cels.2016.07.001 • D.J. Arenillas, A. Forrest, H. Kawaji, T. Lassman, the FANTOM consortium, W.W. Wasserman+, and A. Mathelier+. CAGEd-oPOSSUM: motif enrichment analysis from CAGE-derived TSSs. Bioinformatics, 2016. doi: 10.1093/bioinformatics/btw337
Postdoctoral Fellow Aziz Khan
PhD Student
Marius Gheorghe
Master Student
Eleftherios Pavlos (Erasmus student, Oct. 2016-Mar. 2017)
COLLABORATIONS Vessela Kristensen, Oslo University Hospital Hege Russness, Oslo University Hospital Benoît Ballester, French Institute of Health and Medical Research, Paris, France Charles-Henri Lecellier, Institute of Molecular Genetics of Montpellier, France FANTOM consortium (JASPAR project) Groups of: Wyeth Wasserman, University of British Columbia, Vancouver, Canada Boris Lenhard, Imperial College London, UK Albin Sandelin, Copenhagen University, Denmark
The group’s paper, “DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo” has been highlighted in Cell Systems with a preview article by G.D. Stormo and B. Roy (http://www.cell.com/cell/ abstract/S2405-4712(16)30294-0). The same paper (“DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo”) has been featured during ECCB 2016: the 15th European Conference in Computational Biology with a highlight talk. A series of seminars, the Sven Furberg Seminars in Bioinformatics and Statistical Genomics (http://www. mn.uio.no/ifi/english/research/networks/clsi/seminars/), for which Anthony Mathelier has received funding from UiO:Life Science, were officially launched in March 2017.
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RESEARCH GROUPS
RESEARCH GROUPS
Sandra Lopez-Aviles
Cell Cycle Regulations Group The Group’s main research interest is the study of cell cycle regulation, in particular transitions into and out of mitosis. Classically, the focus of attention in the field has been on understanding the processes regulated by protein kinases (especially Cyclin-Dependent Kinases or CDKs) and on how their activity is temporally and spatially regulated for an ordered cell cycle progression. In our laboratory, however, we are interested in the role of the CDK opposing activity, that is, protein phosphatases. We focus our efforts in studying the processes regulated by protein phosphatases that are relevant to cell cycle progression, and that could have a repercussion on our understanding of the cell cycle.
DESCRIPTION OF THE GROUP’S RESEARCH Cell cycle control is very intricate; it is modulated by external and internal stimuli, and transitions between the different phases are prompted by the engagement of feedback loops. Although phosphatase activity has been assumed to participate in this control, its role has been commonly regarded as non-regulated. This perception is, however, changing, and new data is accumulating in favour of a controlled phosphatase activity timing the events of the cell cycle. Nevertheless, protein phosphatases are still difficult to study due to their pleiotropic effects in the cell and, in this regard, the use of more simple organisms is key to understand their basic functions. With this idea in mind, we have developed our research using a yeast model, Schizosaccharomyces pombe, and looking at individual phosphatase complexes during specific phases of the cell cycle or cellular responses. In trying to simplify the picture that we are studying, we can achieve a clearer view of the essential functions of these phosphatases and ultimately extrapolate them to more complex scenarios.
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More specifically, we are interested in understanding:
Regulation of mitotic progression by protein phosphatases, particularly type-2A phosphatases
We examine the role of phosphatase activity in the ordering of Cdk-substrates dephosphorylation, as well as in the engagement of feedback loops that lead to the irreversible inactivation of Cdk complexes during mitotic exit. We also investigate how phosphatase activity influences the behaviour of cells during a sustained mitotic arrest. Since cells arrested in mitosis for long periods eventually undergo programmed cell death, understanding the mechanisms that can prolong this arrest will be instrumental in order to improve the efficacy of current cancer treatments.
Interplay between phosphatase activity and signalling pathways regulating cell growth and differentiation
We have shown that the phosphatase PP2A-B55 plays an important role in connecting the activities of the two TOR complexes, TORC1 and TORC2. This becomes particularly relevant during nutritional deprivation, a signal that in yeast leads to cellular differentiation. Given this special relation between TOR signalling and PP2A, we are now studying the implication of PP2A activity in other processes regulated during nutritional stress by TOR signalling. In particular, we are addressing the involvement of PP2A in the regulation of protein translation, as well as in the regulation of epigenetic marks and gene transcription.
Mechanisms controlling cell cycle arrest during cellular differentiation
In yeast as in mammals, cell differentiation can only occur if cells have previously stalled their progression through the cell cycle in G1 phase. Hence, differentiation signals control the activity of key proteins involved in cell division. We are trying to understand the mechanisms that lead to this control, specifically in the context of nutrient sensing. The same mechanisms should be relevant to understand how the cell regulates the length of the different cell cycle phases in response to different nutritional inputs.
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PHOTO: JO MICHAEL
RESEARCH GROUPS
ACHIEVEMENTS IN 2016 Our group’s key achievement was the publication of our work in Current Biology: Martin-Martin, R., Portantier, M., Chica-Balaguera, N., Nyquist-Andersen, M., Mata, J., Lopez-Aviles, S. A PP2A-B55-mediated crosstalk between TORC1 and TORC2 regulates the differentiation response in fission yeast. (Current Biology, 2017 Jan 23; 27(2):175-188)
FUNDING In addition to support from NCMM, the Lopez-Aviles Group has, in 2016, received additional support from: • The Norwegian Cancer Society • EU, FP7 Scientia fellows, co-fund through FP7 Marie Curie Actions • The Research Council of Norway
GROUP MEMBERS Engineer
Mari Nyquist-Andersen
Postdoctoral Fellows
Dr. Nathalia Chica-Balaguera Dr. Marina Portantier
Researcher
Ruth Martîn Martîn
COLLABORATIONS Dr. Juan Mata, University of Cambridge, UK Dr. Beata Grallert, Institute for Cancer Research, Radium Hospital, Oslo, Norway Dr. Maria Hernandez-Valladares, PROBE, University of Bergen, Norway Dr. Damien Coudreuse, Institute of Genetics and Development of Rennes, France Dr. Nikolina Sekulic, NCMM
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RESEARCH GROUPS
Camila Vicencio Esguerra
Chemical Neuroscience Group Dr. Esguerra´s research team is focused on exploring the fundamental mechanisms underlying brain function in health and disease. Research focus
Using a combination of genetic and chemical approaches in zebrafish, the group seeks to elucidate the mechanisms of seizure generation, epileptogenesis and treatment resistance by probing the function of novel disease-associated gene variants involved in the etiology of pharmacoresistant epilepsies. The Esguerra Group is using engineered zebrafish mutants and transgenic reporter lines as well as pharmacological seizure models for carrying out in vivo chemical modifier screens to identify novel neuropharmacological tools and drug leads. These models and neuroactive small molecules will serve as valuable tools towards understanding the development, function, and diseases of the brain.
Aims:
1. Generate novel pharmacoresistant zebrafish epilepsy models 2. Functionally confirm disease-causative gene variants in vivo (genotype-phenotype correlation) 3. Identify bioactive small molecules with potential utility as anti-epileptic drug leads and pharmacological tools 4. Elucidate mechanisms of action of identified small molecules
ACHIEVEMENTS IN 2016 David Ramonet awarded the Scientia Marie Curie Postdoctoral Fellowship.
FUNDING In addition to support from NCMM, the Esguerra Group has, in 2016, received additional support from: • NFR (DigiBrain project, Zebrafish work package): Three year PhD student fellowship, plus running costs • EU/UiO Marie Curie Scientia Postdoctoral fellowship: Two year postdoctoral fellowship, plus running costs; Mechanism of action of novel anticonvulsant compound • NFR (NOR-OpenScreen): Automated Zebrafish Behavioral Tracke, Fluorescence Stereomicroscope
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GROUP MEMBERS Head Engineer Rønnaug Steen Kolve Postdoctoral Fellows David Ramonet-Jimenez (from September 2016) Ettore Tiraboschi Research Technician Daniel James Wrobleski (from February 2016) MSc Students Gezime Seferi (from February 2017) Anna Thao Nguyen (from August 2016 until May 2017)
COLLABORATIONS Prof. Holger Lerche, Hertie Institute for Neuroscience, University of Tuebingen, Tuebingen, Germany Functional analysis of novel gene variants associated with epileptic encephalopathies Prof. Sanjay Sisodiya, University College London, London, UK Functional analysis of novel gene variants associated with photosensitive epilepsies Prof. Andreas Turski, Medical Univ. of Lublin, Lublin, Poland Epileptogenic mechanisms of chemoconvulsant compounds Prof. Anne Simonsen, University of Oslo In vivo functional analysis of autophagy genes Prof. Thomas Arnesen, University of Bergen N-Acetyltransferase (NAT) and NAT inhibitor function in vivo Prof. Kjetil Taskén & Dr. Judith Staerk, NCMM Zebrafish as a model for cancer drug sensitivity screening Prof. Marianne Fyhn (Coordinator) et al., University of Oslo DigiBrain (elucidating molecular mechanisms of Schizophrenia)
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RESEARCH GROUPS
Nikolina Sekulic
Structural Biology and Chromatin Group DESCRIPTION OF THE GROUP’S RESEARCH
ACHIEVEMENTS IN 2016
The Sekulic Group uses modern biophysical methods in combination with structural and cell biology to answer important questions in the field of chromatin biology.
The Group officially started at NCMM in January 2016, with the appointment of Nikolina Sekulic from the University of Pennsylvania. Group and lab established with the appointment of a senior researcher and principal engineer.
The group is particularly interested in the centromere the part of the chromosome that governs chromosome segregation during cell division. On average, one hundred billion cells divide in our body every day. Throughout this division and replication, our cells will each retain the same number of chromosomes, with genes faithfully carrying our genetic code. The group’s research is helping to build a better picture of what exactly keeps our genome safe throughout this process. Dr. Sekulic’s previous work in the lab of Professor Ben Black at the University of Pennsylvania has set the foundation for biochemical understanding of centromeres by providing the first high-resolution structure of specialised histone (CENP-A) that is defining these chromosome loci. The Sekulic Group is interested in understanding what unique properties of this histone are generating specialised chromatin at centromeres. Furthermore, the group is working on building a better understanding of the role of other centromere-associated proteins and dynamics of their association with centromere during cell division. The research will also help with further understanding the basic mechanisms that underlie how genetic information is maintained through division and duplication as well as the processes that lead to cancer. These findings will hopefully provide possible new avenues for fighting the disease.
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Lab equipment was installed, including an INFOS shaker that can incubate up to 10L of bacterial media, AKTA pure system, Akta Prime system and Bio-Rad PrepCell system for protein purification, Agilent Carry 60 UV-Vis spectrophotometer with 16-cells holder for enzyme kinetics and much more. Nikolina was awarded a UiO infrastructure grant to purchase an instrument to measure hydrogen-deuterium exchange in proteins that is monitored by mass spectrometry (HDX-MS). • This is a powerful technique that provides dynamic information about proteins and protein complexes • This instrument is the first one of its kind in Norway, and Nikolina’s group will lead in establishing this powerful technique in the country • The instrument will be available for use to other groups in UiO and in the rest of the country Nikolina was nominated by fellow NCMM member, Dr. Preben Morth, as Norwegian representative member for eCOST action BM 1403 “Native mass spectrometry and related methods for structural biology”. This will help her to build links with the European mass spectrometry community, which is working on establishing and
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RESEARCH GROUPS: NIKOLINA SEKULIC
developing methods like HDX-MS. Nikolina was invited to eCOST meeting in Greece in March 2017 where she presented her previous work involving use of HDX-MS Nikolina was awarded a 3-year Young Talent Award from the Norwegian Research Council to study the molecular basis for genome stability. The grant focuses on structural and biochemical studies of protein shugoshin that is responsible for holding duplicated chromosomes together through process of cell division assuring equal segregation in daughter cells. This money will be used to expand the group and secure the necessary resources for research.
Key Publications from Nikolina Sekulic
Several publications from Nikolina’s work at University of Pennsylvania were published during the year, including: Sekulic N, Black BE. Preparation of Recombinant Centromeric Nucleosomes and Formation of Complexes with Nonhistone Centromere Proteins. Met Enzymol. 2016 2016;573:67-96. doi: 10.1016/ bs.mie.2016.01.014.
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FUNDING In addition to support from NCMM, the Sekulic Group has, in 2016, received additional support from: • University of Oslo – Infrastructure Grant • The Research Council of Norway – Young Talent Award
GROUP MEMBERS Principal Engineer
Stine Malene Hansen Wøien
Postdoctoral Fellow Dario Segura-Peña
COLLABORATIONS Sandra Lopez-Aviles, NCMM Ben Black, University of Pennsylvania, USA Benjamin Garcia, University of Pennsylvania, USA
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RESEARCH GROUPS
Irep Gözen
Bionanotechnology and Membrane Systems The Gözen Group uses soft biomaterials, such as lipid membranes, to mimic the behaviour of living cells. By modelling a complex cell with minimal forms in experiments, the group aims to gain a deeper understanding of certain biological processes, including migration (taxis), mechanical damage and repair, endoplasmic reticulum dynamics, and others. The findings from these investigations are applied to design surface-adhered, simple, responsive objects, which are programmable by chemical or physical stimuli. These systems may find value in therapeutic applications or for mitigating environmental hazards.
DESCRIPTION OF THE GROUP’S RESEARCH Membrane fractures
Biological membranes often form circular pores, but they can sometimes break like rigid materials. What determines the pattern formed by a rupturing biomembrane? Why do these fractures sometimes follow dynamics similar to those observed in earthquakes? How can we control pore formation and sealing in the plasma membrane? The group is investigating these and related questions.
Artificial taxis
Cell migration can be stimulated by chemicals, temperature gradients, and even electromagnetic fields. In this project, the group is interested in building cell-like constructs which can migrate in response to specific environmental cues. Can we build simple, motile lipidic capsules inspired by biological cells? Can these be sensitive to specific compounds in the environment, such as microbial agents, pollutants, or debris in blood vessels? The group’s goal is to engineer programmable structures to achieve this.
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Endoplasmic reticulum dynamics
The endoplasmic reticulum (ER) consists of a complex, three-dimensional mesh of lipidic tubular structures, in which the arrangement of tubes changes rapidly over time. The function of ER relies on its peculiar morphology and dynamics. However, it is challenging to directly measure its properties in cells as a function of time. A better understanding is needed of ER dynamics, the degradation of which has been linked to neurological disorders including Alzheimer’s disease. To address this problem, the group is fabricating an artificial ER-like network, free of proteins and other intracellular elements. To what extent are these dynamics determined by the material properties of the lipid? What is the impact of Ca2+ in the tubular re-arrangements? The group’s artificial system will shed light on these and related questions.
ACHIEVEMENTS IN 2016 Group leader Irep Gözen started in September 2016. In the short amount of time since the start-up of this group, progress has been made on: • Receiving external funding • Initiating plenty of local collaborations • Purchasing and the installation of a state-of-the-art laser scanning confocal microscope Other laboratory-related arrangements and research articles are in progress, and interviews regarding hiring for the Group are also ongoing.
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RESEARCH GROUPS: IREP GÖZEN
Foto: Irep Gözen
FUNDING
COLLABORATIONS
In addition to support from NCMM, the Gözen Group has, in 2016, received additional support from:
Alar Ainla, Harvard University, USA Vinothan N. Manoharan, Harvard University, USA Michael Taylor, Santa Clara University, USA Aldo Jesorka, Chalmers University, Sweden Paul Dommernes, NTNU, Norway Jon Otto Fossum, NTNU, Norway Marcella Orwick Rydmark, UiO
• Vetenskapsrådet (Swedish Research Council) • Awarded Convergence Environment funding from UiO: Life Science. Irep Gözen will lead the Programmable Cell-like Compartments convergence environment.
GROUP MEMBERS Expected member: Ilayda Kantarci, Istanbul Technical University (Erasmus Plus Trainee Programme), JuneSeptember 2017 Two PhD students, hiring for 2017-2021 in progress One Postdoc, hiring for 2017-2021 in progress. Initially one year, with the possibility to extend for three more years. Employer: Chalmers University, Sweden
Consortium 1: Prof. Harald Stenmark, Prof. Andreas Carlson & Dr. Gry Oftedal: UiO: Funding application pending. Consortium 2: Ute Kengel, Kirsten Sandvig, Michele Cascella & Clare Shelley-Egan: UiO. Funding application pending. Consortium 3: Staale Petter Lyngstadaas, Gry Oftedal, Dirk Linke, Reidar Lund & Sandip Kanse: UiO. Funding application pending. Consortium 4: Sören Abel & Preben Morth: UiO
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NCMM Associate Investigators and Young Associate Investigators NCMM aims to continue and develop its scientific community and knowledge capabilities, through establishing strong collaborative links with key scientists and research groups across Norway. These links and collaborations greatly support translational networking. NCMM’s Associate Investigators
NCMM’s Associate Investigators are drawn from a group of outstanding scientists currently based in Norway, with expertise that is compatible with NCMM’s research areas, and who are interested in collaborating with NCMM. Associate Investigators contribute their expertise in molecular and translational medicine, and to support newly recruited young NCMM Group Leaders and Young Associate Investigators through mentoring activities.
Young Associate Investigators
NCMM has initiated a programme for young, talented researchers that are recruited as Group Leaders at other institutions. Young Associate Investigators are recruited through one of the two following channels: 1. Direct application to NCMM in response to open calls 2. Through universities and other research institutions that wish to recruit young, talented Group Leaders and where the conditions are similar to those offered to NCMM Group Leaders. An affiliation to NCMM can then be offered during the call and NCMM will be involved in the recruitment process. Associate and Young Associate Investigators continue to work at their host institutions, but are credited an affiliation to NCMM and the Nordic EMBL Partnership.
NCMM Associate Investigators:
• Professor Lars Akslen, Centre for Cancer Biomarkers (CCBIO), University of Bergen and Haukeland University Hospital • Professor Ole A. Andreassen, Division of Mental Health and Addiction, Oslo University Hospital and
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Institute of Clinical Medicine, University of Oslo • Professor John-Bjarne Hansen, KG Jebsen – Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT, The Arctic University of Norway and University Hospital of North Norway • Professor Arne Klungland, Department of Microbiology, Division of Diagnostics and Intervention, Institute of Clinical Medicine, Oslo University Hospital and Institute for Basic Medical Sciences, University of Oslo • Professor Per E. Lønning, Section of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital • Professor Karl-Johan Malmberg, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and Institute for Clinical Medicine, University of Oslo • Professor Erlend Nagelhus, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo and Department of Neurology, Oslo University Hospital • Professor Pål R. Njølstad, KG Jebsen Centre for Diabetes Research, University of Bergen and Department of Pediatrics, Haukeland University Hospital • Professor Johanna Olweus, KG Jebsen Center for Cancer Immunotherapy, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo • Professor Ole P. Rekvig, Department of Medical Biology, University of Tromsø and University Hospital of Northern Norway • Professor Anne Simonsen, D epartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo • Professor Anders Sundan, Department of Cancer Research and Molecular Medicine, Norwegian University for Science and Technology (NTNU)
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NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS
NCMM Young Associate Investigators:
NCMM has, through the NCMM Programme for Networking with Associate and Young Associate Investigators, allocated funding for collaborative projects between NCMM research groups and Associate Investigators and Young Associate Investigators.
• Dr. Sören Abel, Department of Pharmacy, University of Tromsø and Harvard Medical School • Dr. Thomas Arnesen, Department of Molecular Biology, University of Bergen and Department of Surgery, Haukeland University Hospital • Dr. Lorena Arranz, Department of Medical Biology, University of Tromsø and Department of Hematology, University Hospital of Northern Norway (UNN) • Associate Professor Simona Chera, Department of Clinical Science, University of Bergen • Professor Trude H. Flo, Centre of Molecular Inflammation Research (CEMIR) and Dept. of Cancer Research and Molecular Medicine, Norwegian University for Science and Technology (NTNU) • Dr. Espen Melum, Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital • Associate Professor Siver Mostue, Department of Circulation and Medical Imaging and Department of Laboratory Medicine, Norwegian University for Science and Technology (NTNU) • Dr. Hege Russnes, Department of Pathology and Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital • Dr. Pia Abel zur Wiesch, Department of Pharmacy, University of Tromsø and Yale School of Public Health, US
These grants are designed to act as seed money for new collaborative projects. Three calls were announced in the first five year period of NCMM (2010-2014). A fourth call allocating up to five million NOK was announced at the end of 2016.
In 2017, ten new collaborative projects have received funding from NCMM: Grant allocations from NCMM Programme for networking with Associate Investigators and Young Associate Investigators, 2017 Associate Investigator(s)/ Young Associate Investigator(s)
Collaborating NCMM group(s)
Granted (kNOK) this call
Project Title
Sören Abel
Irep Gözen / Preben Morth
700
Dynamics of Protein-Lipid Interaction
Thomas Arnesen
Camila Esguerra
300
The physiological impact of N-terminal transferases in Danio rerio – a combined morpholino and inhibitor screen
Lorena Arranz
Judith Staerk
650
Mouse xenograft assays to assess the functionality of hESC and iPSC-derived CD34+ cells
Trude H. Flo
Landskron (KT group)
250
Innate immune activation in CD4+ T-cells
Karl-Johan Malmberg
Judith Staerk
400
Genetic and functional analysis of hESC and CD34+-derived blood lineage cells
Espen Melum
Aandahl (KT group)
200
Mucosal associated invariant T-cells during bile duct inflammation
Erlend Nagelhus
Preben Morth
400
Carbonic anhydrase 4 as a drug target in neurological disorders with fluid dyshomeostasis
Hege Russnes
Anthony Mathelier
480
The molecular mechanism and impact of transition from diploid to aneuploid cells in cancer
Anne Simonsen
Camila Esguerra
600
Role of NIPSNAP1 in zebrafish development and disease
Anne Simonsen
Preben Morth
500
Structural and functional characterization of Sorting nexin 18 (SNX18)
TOTAL
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4480
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Research Collaboration with Oslo University Hospital The overall objectives of NCMM are to conduct cutting-edge research in molecular medicine, and facilitate translation of discoveries in basic medical research into clinical practice. To enable translational research, NCMM has developed strong links to South-Eastern Norway Regional Health Authority and its subsidiary Oslo University Hospital (OUH).
All NCMM Translational Research Group Leaders have adjunct positions in clinical or para-clinical departments at OUH. Our experience with these affiliations is that they facilitate clinical collaborations, give group leaders better access to patient materials, biobanks and clinical trials, and that they are crucial to facilitate translational research. These research collaborations have already resulted in a number of joint publications. NCMM Group Leaders also report on several joint applications for funding of new collaborative projects. NCMM Group Leaders currently hold adjunct appointments at the following departments:
Department of Infectious Diseases (OUH)
NCMM PI: K. TaskĂŠn The department is the largest of its kind in Norway. It covers the entire field of infectious medical conditions, such as tropical medicine, HIV, and tuberculosis, as well as severe and life threatening bacterial and viral infections. The Department of Infectious Diseases runs
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an extensive research programme, especially related to the diseases HIV/AIDS and hepatitis. The department is also responsible for a variety of advanced educational courses in infectious diseases and is organised under the Medicine Division at OUH.
Department of Molecular Oncology, Institute for Cancer Research (OUH)
NCMM PI: I. Mills The Institute for Cancer Research has strong international research groups within biochemistry, cell and tumour biology, genetics, radiation biology, immunology, and cancer prevention. For more than 30 years there has been a close interaction between researchers at this institute and cancer surgeons, oncologists, and pathologists. The emphasis on translational science has resulted in numerous clinical protocols based on in-house research and the institute is a key partner in the Comprehensive Cancer Centre, organisationally under the Division of Cancer Medicine, Surgery and Transplantation at OUH.
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NCMM ASSOCIATE RESEARCH INVESTIGATORS COLLABORATION AND YOUNG WITH OSLO ASSOCIATE UNIVERSITY RESEARCH INVESTIGATORS HOSPITAL GROUPS
Department of Cancer Genetics, Institute for Cancer Research (OUH)
NCMM PIs: A. Hurtado, A. Mathelier The main goal of the department is to follow the linear time course of predisposition, initiation, early stages and advanced disease, and to dissect the molecular mechanisms triggered at each stage. Furthermore, the department is focusing on how to follow the multi-dimensional interactions at various levels in a systems biology approach to better perform risk estimation, prognostication, and prediction.
Institute for Experimental Medical Research (OUH)
NCMM PI: J. P Morth The Institute for Experimental Medical Research primarily focuses on heart disease research and teaching. In particular, the institute performs research on congestive heart failure, with a special interest in heart electrophysiology and membrane pumps. The institute is involved in extensive collaborations with other laboratories in clinical departments at the OUH, and interacts with colleagues nationally and internationally. The institute is organised under the Division of Cardiovascular and Pulmonary Disease at OUH.
of high international standard. Furthermore, the department conducts research in most of the areas in which treatment is provided. The department is organised under the Division of Cancer Medicine, Surgery, and Transplantation at OUH. On his appointment to NCMM, Hartmut Luecke will take up an adjunct position at the Department of Medical Biochemistry as Oslo University Hospital
Research Collaborations with University of Oslo
All NCMM Biotechnology Group Leaders hold adjunct positions at the following departments: School of Pharmacy Camila Vicencio Esguerra Department of Chemistry Irep GĂśzen and Nikolina Sekulic Department of Biosciences Sandra Avilez-Lopes
Department of Haematology, (OUH)
NCMM PI: J. Staerk Patients with all types of blood diseases are treated at the Department of Haematology. The department’s goal is to deliver excellent patient care, provide advanced teaching in the field of blood diseases and perform research
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From Disease Mechanisms to Clinical Practice NCMM group leaders have so far listed some 27 on-going operational and interventional clinical studies in the fields of therapy and disease mechanisms as well as in the molecular markers, diagnostic and monitoring areas. On-going development in the area of therapy
• Immunomodulating cAMP antagonists and PKA anchoring disruptors (immunodeficiency and anti-tumor immune responses). • Disruption of the PKA-AKAP18-phospholambanSerca2 complex for cardio-protective effect in ischemia-reperfusion damage. • Small molecule inhibitors of OGlcNAc tranferase and de novo purine biosynthesis enzymes to destabilize oncogenic signaling in prostate cancer. • Bromodomain inhibition to enhance responses to androgen deprivation/anti-androgens in prostate cancer. • Targeting of Na+/K+-ATPase and Serca2 in neurobiology and heart disease. • Suppression mechanisms by regulatory T cells with application in immune diseases, autoimmunity and cancer. • iPSC disease-modeling of blood disorders. • Assay development and structural analysis of the membrane proteins in virulence operon mgtCBR specific to pathogenic bacteria. • Structural analysis of the membrane proteins linked to the virulence operon mgtCBR specific to pathogenic bacteria. • Structural analysis of bicarbonate transporters and investigation of pH homeostasis • Enzymatic detection and quantification assay of isatin, a putative stress biomarker in blood. • Investigation of the Membrane-associated RING finger protein (MARCH) E3-ligases. • Cancer drug sensitivity screening on patient samples with set of approx. 400 cancer drugs to assist clinical decision on individualized therapy choices in chronic lymphatic leukemia, multiple myeloma and ovarian cancer. • Elucidation of the mechanism of action of medroxiprogesterone injection before surgery as a treatment that improves overall and disease-free survival of ER+/ HER2- breast cancer patients. • Development of CAMKK2 inhibitors for the treatment of prostate cancer.
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On-going development in the area of diagnostics and monitoring
• Prostate cancer markers – serum/plasma protein biomarkers, overlapping genetic risk factors for prostate cancer and blood lipid traits, transcript-based biomarkers in urine and circulating tumor cells. Evaluation of protein biomarkers in blood samples from patients with prostate cancer undergoing radiotherapy with or without androgen deprivation therapy. Further evaluation of blood-based protein biomarkers in relation to outcomes from surgery and radiotherapy. • New biochemical markers for MAO diseases & early screen Parkinson. • Single cell analysis of inflammatory signaling events by fluorescent cell bar-coded phospho-flow cytometry for diagnostics and monitoring • Regulatory T cell markers in HIV and other immune diseases. • Flow cytometry-based biomarkers in mitogenic signaling pathways for drug sensitivity screens. • Signalling responses in peripheral T cells from colorectal cancer patients are affected by high concentrations of circulating prostaglandin E2. • Ongoing observational study on chronic lymphatic leukaemia (CLL) and multiple myeloma (MM). • Observational studies on asthma and chronic obstructive lung disease inflammatory component. • Observational studies on HIV long-term non-responders. • Interventional study on COX-2i and vaccine in TB patients.
Proof-of-concept in humans
• Effect of anti-inflammatory drug (COX-2 inhibitor Phase IIA) on immune function (CD38 o.a.) and vaccine responses in HIV-infected patients. (Recent publication, Prebensen et al. May 2017). • Secondary preventive effect of acetyl salicylic acid in metastatic colorectal cancer. Furthermore, NCMM is involved in two translational KG Jebsen Research Centres that were established in 2013. NCMM is connected to the KG Jebsen Centres Inflammation Research (led by Prof. Guttorm Haraldsen) and Cancer Immunotherapy (led by Prof. Johanna Olweus).
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RESEARCH HIGHLIGHTS
Research Highlights Study into effects of aspirin on colorectal cancer patients with liver metastases As reported in the 2015 NCMM Annual Report, a study by NCMM’s Taskén Group into how aspirin affects the survival rates of patients with colorectal cancer (CRC), was published in the Journal of Clinical Oncology. The paper, with Simer J. Bains as first author and Kjetil Taskén as last author, presented the data from a large cancer registry study that coupled data with the Norwegian Cancer Registry and the Norwegian Prescription Database. It was found that aspirin exposure after diagnosis of CRC was independently associated with an improved survival rate of colorectal cancer-specific survival, as well as overall survival.
The interplay between TORC1 and TORC2 complexes, and their role in processing nutritional cues to regulate cellular behaviour Growing cells integrate a variety of cues in order to decide whether conditions are favourable for cell division, or whether they have to halt their cell cycle and differentiate. Failure to do so has negative implications in the fitness of the organism. For example, cancer pathogenesis is often associated with the poor capacity of cancer cells to differentiate.
CRC affects around 4000 people in Norway each year, and half of these patients will see the cancer spread to their liver. The findings from the initial retrospective study by Bains et al were such that a new multicentre, intervention study has been initiated to explore the effects of aspirin on patients suffering from CRC that have also had surgically-remove liver metastases. 19m NOK has been awarded to the project by KLINBEFORSK (Department of Health and Social Services) for 2017-2021, alongside 12m NOK funding from the Cancer Society and The Research Council of Norway. NCMM Director Kjetil Taskén will co-lead the study, alongside Bjørn Atle Bjørnbeth at Oslo University Hospital and Sheraz Yaqub at UiO. Around 700 patients will be observed in the study; around half will take aspirin each day with the other half receiving a placebo. The study aims to explore whether aspirin use has an impact on the survival rates of those prescribed aspirin. All Norwegian university hospitals that treat patients with CRC that has spread to the liver will participate, including: Oslo University Hospital Stavanger University Hospital University Hospital of North Norway Tromsø St. Olav’s Hospital in Trondheim Haukeland University Hospital in Bergen
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Figure legend: Graphical Abstract
The TORC1 and TORC2 complexes play important roles in integrating nutritional cues to activate transcriptional programmes and thereby regulate cellular behaviour. However, the interplay between these complexes has, until now, been poorly understood. To address this issue, Lopez-Aviles and colleagues used the fission yeast Schizosaccharomyces pombe to investigate how phosphatase activity participates in the interplay between the TORC1 and TORC2 complexes during the switch from proliferation to sexual differentiation. Lopez-Aviles and colleagues found that loss of the phosphatase PP2A-B55Pab1 enhances the expression of differentiation-specific genes and leads to premature conjugation. Deletion of pab1 brings about a transcriptional profile similar to TORC1 inactivation, and also overcomes the repression of differentiation genes in cells overexpressing TORC1. Importantly, it was possible to show that this effect is mediated by an increased TORC2-AKT (Gad8) signalling.
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RESEARCH HIGHLIGHTS Under nutrient-rich conditions, PP2A-B55Pab1 dephosphorylates Gad8 Ser546, repressing its activity. Conversely, TORC1 inactivation upon starvation leads to the inactivation of PP2A-B55Pab1 through the GreatwallEndosulfin pathway. This results in the TORC2-mediated activation of Gad8 and the commitment to differentiation. In summary, PP2A-B55Pab1 enables a crosstalk between the two TOR complexes that controls cell-fate decisions in response to nutrient availability. In the future, more exhaustive studies of PP2A-B55Pab1 and Gad8 targets will be fundamental to understand how these signalling nodes modulate the differentiation process. The full article, A PP2A-B55-Mediated Crosstalk between TORC1 and TORC2 Regulates the Differentiation Response in Fission Yeast, can be found in Current Biology 2017 Jan 23; 27(2): 175–188. doi: 10.1016/j.cub.2016.11.037
CTCF emerges as a new player in transcription factors regulating gene expression during breast cancer progression This study from the Hurtado Group reveals an important, unanticipated interplay between the transcriptional regulator CCCTC-binding factor (CTCF) and nuclear lamina that control the transcription of ER target genes. CTCF is an ubiquitous multivalent zinc finger protein that regulates higher-order chromatin organisation. Here, Hurtado and colleagues show that CTCF plays an active role in moderating gene transcription induced by estrogen through its direct interaction with transcriptionally active chromatin-regions. Enhancer regions and transcription start sites of estrogen-target regulated genes are connected by means of Estrogen Receptor (ER) long-range chromatin interactions. Yet, the complete molecular mechanisms controlling the transcriptional output of engaged enhancers and subsequent activation of coding genes remain elusive. Hurtado and colleagues have found that CTCF binding to enhancer RNAs is enriched when breast cancer cells are stimulated with estrogen. CTCF binding to enhancer regions results in modulation of estrogen-induced gene transcription by preventing ER chromatin binding and by hindering the formation of additional enhancer-promoter ER looping. Furthermore, the depletion of CTCF facilitates the expression of target genes associated with cell division and increases the rate of breast cancer cell proliferation. Hurtado and colleagues have also uncovered a genomic network connecting loci enriched in cell cycle regulator genes to nuclear lamina that mediates the CTCF function. The nuclear lamina and chromatin interactions are regulated by estrogen-ER. Hurtado and colleagues have
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observed that the chromatin loops formed when cells are treated with estrogen establish contacts with the nuclear lamina. Once there, the portion of CTCF associated with the nuclear lamina interacts with enhancer regions, limiting the formation of ER loops and the induction of genes present in the loop. Collectively, results from the Hurtado Group’s research reveal an important, unanticipated interplay between CTCF and nuclear lamina to control the transcription of ER target genes, which has great implications in the rate of growth of breast cancer cells. CTCF emerges as a new player in the intricate network of transcription factors regulating gene expression during breast cancer progression. The full article, CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions, can be found on Nucleic Acids Research, 2016, 44 (22): 10588-10602. DOI: https://doi.org/10.1093/ nar/gkw785
Top talent recruited to NCMM NCMM has significantly added to its breadth of research expertise with the appointment of three new, young Group Leaders and a new Assistant Director. Nikolina Sekulic, Irep Gözen, and Anthony Mathelier all joined the Centre in 2016. Nikolina Sekulic was recruited from the lab of Professor Ben Black at the University of Pennsylvania in January, and has set up the Structural Biology and Chromatin Group. Dr. Sekulic’s previous work in Pennsylvania has set the foundation for biochemical understanding of centromeres by providing the first high-resolution structure of specialised histone (CENP-A) that is defining these chromosome loci. Anthony Mathelier was recruited from the group of Dr. Wyeth Wasserman at the University of British Columbia, Vancouver, Canada, where he was deputy group leader. Anthony started in May 2016 and is now the Group Leader of the Computational Biology and Gene Regulation Group at NCMM. The Mathelier Group develops and assesses computational methods to analyse genomic sequences (DNA). The goal of the group is to create the next generation of cutting-edge algorithms and open computational biology software, with immediate application to real-life biological problems. Irep Gözen was recruited from the Manoharan Lab at Harvard University to set up the Bionanotechnology and Membrane Systems Group. Dr. Gözen started in September 2016 and the group uses soft biomaterials, such as lipid membranes, to mimic the behaviour of living cells. By modelling a complex cell with minimal forms in experiments, the group aims to gain a deeper understanding of certain biological processes, including
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migration (taxis), mechanical damage and repair, endoplasmic reticulum dynamics, and others. Additionally, as discussed earlier in this annual report, the appointment of NCMM Assistant Director, Professor Hartmut Luecke, (due to officially join NCMM in November 2017), from University of California, Irvine, USA, will contribute hugely to the structural biology community in Oslo.
will add further excellence to the quality of basic biological research conducted at both NCMM, and in the wider context of the Nordic EMBL Partnership.
The recruitment and appointment of these four extremely talented researchers to NCMM further strengthens our status as a greenhouse for the nurturing and development of international research talent. All four have been recruited back to Europe from the USA and Canada, and they and their research groups
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News and events NCMM Network Meeting
The inaugural NCMM Network meeting took place in January. The meeting was aimed at NCMM Group Leaders, newly and re-appointed Associate Investigators
and Young Associate Investigators, Board members, and other stakeholders and scientific leaders.
NCMM Network Meeting 2016. Photo: Johannes Landskron, NCMM
JANUARY 2016
JUNE
The Nordic EMBL Partnership Meeting. Photo: EMBL
Nordic EMBL Partnership
The Nordic EMBL Partnership Conference, ‘Perspectives in Translational Medicine’ and EMBL Steering Committee meeting took place at the EMBL headquarters in Heidelberg in June. The three-day meeting involved the other Nordic EMBL Partners, FIMM, MIMS, and DANDRITE, plus other EMBL Partners from across Europe.
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NEWS AND EVENTS
King Olav V Prize for Cancer Research 2016 From the left: The Secretary General of the Norwegian Cancer Society Anne Lise Ryel, HM King Harald V, Prof. Kjetil Taskén and GunnElin Aa Bjørneboe (Chair, Board Cancer Society). Photo: Kreftforeningen
NCMM Director, Professor Kjetil Taskén, received the prestigious King Olav V’s Prize for Cancer Research 2016 during a special ceremony at the University of Oslo on June 6 2016. The prize was presented by King Harald V at the University of Oslo’s Gamle Festsal, on behalf of the Norwegian Cancer Society. Professor Taskén was awarded the highly-coveted prize in recognition of his major contribution to the under-
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standing of immuno-oncology; work which is highly relevant in the development of next-generation of immunotherapy. King Olav V’s Cancer Research Fund, and its associated prize, was established in memory of King Olav V in 1992. Since then the prize has been awarded every year to an outstanding researcher who has distinguished themselves by working to improve the lives of many people. The prize is 1 million NOK.
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NEWS AND EVENTS
SAB Visit
The Scientific Advisory Board (SAB) visited NCMM in October for their fifth visit.
Scientific Retreat
NCMM and the BiO organized a joint scientific retreat to the Holmen Fjordhotell for all employees and students. The two-day retreat included scientific talks and discussions, a social dinner, and outdoor activities.
Holmen Fjord Hotell
OCTOBER
NOVEMBER
PHOTO: JOHANNES LANDSKRON
National PhD Course Molecular Medicine
NCMM organized a national PhD course in molecular medicine in November. Altogether, 35 participants from different institutions in Norway attended this two-week course. The aim of the course is to give participants insights into the translational and clinical aspects of science.
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NEWS AND EVENTS
The merger between NCMM and BiO was formally completed at the start of January.
This marks an exciting development for the Network, bringing together two centres with a shared model. The merger means NCMM is now home to 11 research groups.
JANUARY - FEBRUARY 2017
NCMM Network Meeting
The Second NCMM Network Meeting took place at Forskningsparken.
MARCH
MAY
Convergence Environment Funding
NCMM Director Kjetil Taskén and Group Leader Irep Gözen awarded Convergence Environment funding from UiO: Life Science. Irep Gözen will lead the Programmable Cell Like Compartments Convergence Environment, and Kjetil Taskén will be a co-PI for the Personalised Cancer Therapies (PERCATHE) Convergence Environment led by Arnoldo Frigessi.
Professor Per O. Seglen with Anne Lise Ryel, General Secretary of the Norwegian Cancer Society. Foto: Ingvild Vaale Arnesen/Kreftforeningen
King Olav V Prize for Cancer Research
NCMM Guest Researcher, Professor Per O. Seglen, was announced as the winner of the 2017 King Olav V’s Prize for Cancer Research. Professer Seglen has been awarded the prize in recognition of his pioneering work with autophagy. The prize will be presented in a ceremony on 6 June 2017.
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Attendees at the NCMM Network meeting. Photo: Johannes Landskron, NCMM
NCMM’s Network Meeting 2017
Centre for Molecular Medicine Norway (NCMM) held its annual Network Meeting at Oslo Science Park over 6 and 7 February. The Network Meeting brings together the scientific NCMM network from all over Norway, as well as Board members and other stakeholders. The meeting provides a setting where all members have the chance to catch up and share their expertise, news, and thoughts on the research landscape. Following on from 2016’s inaugural Network Meeting, where several outside speakers presented on more general topics, 2017’s invite-only event mostly saw speakers from within the NCMM network, giving more in-depth talks about their research and the landscape as a whole.
The programme: Day One
The first day of the meeting included talks from NCMM Associate Investigators (AIs), Young Associate Investigators (YAIs), and Group Leaders. Topics covered ranged from the Nobel Prize in Chemistry to in-depth insights into current research at NCMM. The day rounded off with three panel debates, covering topics such as personal career experiences, genomic medicine and gene-editing, and drug repurposing and personalized cancer treatment.
The programme: Day Two
Day Two of the event was open only to NCMM Group Leaders and Associate and Young Associate Investigators. NCMM has allocated up to 5 million NOK for funding concrete collaborative projects between NCMM Group Leaders and AIs/YAIs. This day focused more on allowing Group Leaders to connect with AIs and Young AIs, and to try and find some common ground where collaboration might be interesting. The day included elevator pitch sessions, which led on to an informal ‘speed-dating’ session. NCMM would like to thank everyone who attended and we look forward to welcoming you again for an exciting event in 2018.
A panel debate at the NCMM Network meeting. Photo: Johannes Landskron, NCMM
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NCMM PhD dissertations
NCMM has recruited an international group of PhD fellows, and in 2016 nine PhD candidates from seven different countries defended their thesis at UiO. SIMER J. BAINS
MD Simer J. Bains defended her thesis entitled “Malignancy, Metastasis and Immune Modulation – Experimental Tumor Immune Regulation and Observational Clinical Studies in Ovarian and Colorectal Cancer” in January 2016. The work was performed in the research group of Kjetil Taskén, and Bains defended her thesis at the Faculty of Medicine, UiO.
ELISA FIORITO
Elisa Fiorito defended her thesis entitled “Study of the role of CTCF and FOXA1 in breast cancer” in April 2016 at the Department of Biosciences, Faculty of Mathematics and Natural Sciences, UiO. Fiorito’s research was performed in the research group of Antoni Hurtado.
SARANYA SUBRAMANI
Saranya Subramani defended her thesis entitled “Biochemical character-ization and crystallization of the magnesium transporting P-type ATPase MgtA” in May 2016. The work was carried out in the research group of Jens Preben Morth, and Subramani defended her thesis at the School of Pharmacy, Faculty of Mathematics and Natural Sciences, UiO.
STALIN CHELLAPPA GUNASEKARAN
Stalin Chellappa Gunasekaran defended his thesis entitled “Human Regulatory T cells: Suppressive Function and Role in Pancreatic Cancer and Distal Bile Duct Cancer” in June 2016. The work was completed in the research group of Kjetil Taskén, and Gunasekaran defended his thesis at the Faculty of Medicine, UiO.
THEIS SOMMER
MSc Theis Sommer defended his thesis “Biotechnological application and biophysical characterization of the bacterial enzyme Isatin hydrolase AND Structural studies of the regulatory N-terminal domain of the SLC4 bicarbonate transporter family and characterization of a novel zinc binding,” at the Department of Biosciences, Faculty of Mathematics and Natural Sciences, UiO in June 2016. The research was carried out in the research group of Jens Preben Morth.
ALEKSANDRA DUKIC
Aleksandra Dukic defended her thesis “Role of protein kinase A and the A-kinase anchoring protein Ezrin in regulation of gap junction communication” at Faculty of Medicine, UiO, in December 2016. The research was carried out in the research group of Kjetil Taskén.
LISA GERNER
Lisa Gerner defended her thesis entitled “An Exploration of the Structure and Function of Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) in Prostate Cancer” at the Faculty of Medicine, UiO, in February 2017. Gerner’s work was carried out in the research groups of Ian G. Mills and Jens Preben Morth.
BERTRAND SIMON
Bertrand Simon, a joint student from the EMBL outstation in Hamburg and NCMM, defended his thesis entitled “Structural and functional regulation of death-associated protein kinases activity by calcium/calmodulin binding”. Simon’s research was carried out under the supervision of Ian G. Mills at NCMM and Professor Matthias Wilmanns at EMBL-Hamburg.
NORA V. LIESKE
M.Sc. Nora Valeska Lieske defended her thesis, “Modulation of Adaptive Immune Responses — Studies in infectious diseases and immune disorders” in June 2016. The work was performed in the research group of Kjetil Taskén, and Lieske defended her thesis at Faculty of Medicine at UiO.
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Chair Ragnhild A. Lothe: “The Board is pleased with the decision to merge NCMM and BiO (Biotechnology Centre of Oslo), which was formally put into effect on the 2nd January 2017.” The Centre now hosts two departments: NCMM Translational research and NCMM Biotechnology, with a total of 11 independent groups ensuring less vulnerability for the Centre as a whole. However, it remains a challenge for new group leaders to become fully integrated in the scientific community of Oslo within a reasonable time frame. A challenge we all may contribute to solve. The Board congratulates professor Kjetil Taskén who received the King Olav V’s Prize for Cancer Research in June 2016 in recognition of his, “major contribution to the understanding of immuno-oncology”. Work that will become even more relevant in the development of next-generation immunotherapy. Furthermore, we also congratulate Professor Emeritus Per Seglen at NCMM, who will receive the King Olav V’s Prize for Cancer Research June 2017. This is very well deserved for his groundbreaking research into autophagic-lysosomal protein degradation and its relationship to cancer.
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NCMM Board
NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE RESEARCH INVESTIGATORS GROUPS
Chair of the NCMM Board, Ragnhild A. Lothe with NCMM Director Kjetil Taskén
BOARD MEMBERS The NCMM Board is responsible for, in collaboration with the Director, the Centre’s overall coordination and progress. The Board steers and supervises NCMM’s activities and finances and also approves the Centre’s strategic plans, objectives and budget. The Board’s decisions contribute to promoting excellence in the Centre’s recruitments, research, collaborations, and translational value. The Board consists of the Chair and five members representing NCMM’s host, the University of Oslo and the consortium partner Health South-East Regional Health Authority (HSE), as well as a national representative.
Chair:
Professor Ragnhild A. Lothe, Oslo University Hospital (OUH) and University of Oslo (UiO)
Members:
Professor Jan G. Bjålie, Faculty of Medicine, UiO Professor Finn-Eirik Johansen, Faculty of Mathematics and Natural Sciences, UiO Director Research and Innovation Per Morten Sandset, South-Eastern Norway Regional Health Authority (HSE) Professor Jens Petter Berg, Oslo University Hospital Maria Perander, UiT The Arctic University of Norway (national representative)
Deputy Members:
Professor Hilde Nilsen, Faculty of Medicine, UiO and Akershus University Hospital Head of Research Øystein Krüger, Dept. of Research and Innovation, South-Eastern Norway Regional Health Authority (HSE) Professor Ola Myklebost, University of Bergen (national representative)
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PHOTO: JOHN HUGHES
Scientific Advisory Board (SAB) The NCMM Scientific Advisory Board (SAB) was first appointed in 2011 and, from 2015, the SAB was also appointed as a joint Board for NCMM and the Biotechnology Centre of Oslo, an agreement which will continue.
Professor Richard Treisman – Chair from March 2017 Director of CRUK London Research Institute London, UK Research Director, the Francis Crick Institute London, UK
The SAB’s main mission is to offer academic and strategic advice, as well as benchmark the performance of NCMM’s research groups and the Centre internationally. The SAB meets with NCMM core members every 12-24 months. These meetings allow for review of recent progress and advice on future strategies.
Professor Erich Nigg Director of Biozentrum Basel, Switzerland
The previous SAB visit took place in the autumn of 2016, and the next visit is expected to take place in autumn 2017.
Members of NCMM’s Scientific Advisory Board The SAB consists of six internationally renowned scientists:
Professor Lief Groop (Chair) – until March 2017 Head of Lund University Diabetes Centre Department of Endocrinology Clinical Sciences Malmø Lund University, Sweden
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Dr. Alvis Brazma EMBL Senior Scientist & Senior Team Leader EMBL-EBI Hinxton Cambridge, UK Professor Margaret Frame Science Director and Chair of Cancer Biology Edinburgh Cancer Research Centre Edinburgh, UK Professor Nazneen Rahman Head of Division of Genetics and Epidemiology Institute of Cancer Research London, UK Professor Olli Kallioniemi (from March 2017) Director SciLifeLab Stockholm, Sweden
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NCMM Funding NCMM is in its second five-year period. NCMM core funding in this period is 31 million Norwegian kroner (mNOK) per year from the three consortia partners; UiO, the Research Council of Norway (RCN), and Health SouthEast (HSE). Including transferred funds, NCMM spent 30 mNOK in 2016. This was less than budgeted and was due to some delays in recruitment of a new research group/assistant director.
The decrease in extramural funding in 2016 compared to the last couple of years is a result of research groups rotating out of the Centre in the period 2014-2016. In 2016 three new research groups were recruited to NCMM/BiO, and another group will be established in the fall of 2017. We therefore expect the amount of extramural funding to increase again from 2018 as the new groups become more established.
In January 2017, the merger between NCMM and the Biotechnology Centre of Oslo (BiO) formally came into effect. The new NCMM consists of two departments: NCMM Translational Research (former NCMM) and NCMM Biotechnology (former BiO) with altogether 11 research groups. The core funding for NCMM Translational Research in 2017 is, as before, 31 mNOK per year, whereas NCMM Biotechnology has a core funding of 27.2 mNOK. Furthermore, overheads, income from core facilities, and production-based income are in addition.
Extramural funding for 2017 is so far stipulated to 36 mNOK. In addition, NCMM’s Director is Co-PI on two clinical intervention trials where the funding is placed at the Oslo University Hospital. In 2017 these projects have been funded with altogether 8.75 mNOK from the Research Council of Norway, The Norwegian Cancer Society, and the Norwegian Department of Health and Social Services.
NCMM extramural funding, in the form of grants to the group leaders and other competitive funding, has increased steadily from 7 mNOK in 2010 to 42 mNOK in 2015. In 2016, NCMM reached 32 mNOK in annual grants. This includes grants from the Research Council of Norway, the Norwegian Cancer Society, Health SouthEast, competitive grants at UiO, European Commission, and private foundations and organisations such as the Lundbeck Foundation, Novo Nordisk Foundation, KG Jebsen Centres, amongst others.
23% 35% NCMM Core Funding
2016
UIO RCN HSE
UIO RCN
42%
HSE
5%
3% 5%
6%
7%
RCN
5% 34%
Extramural
21%
Funding Sources
14%
2017
2016 13%
RCN UIO Estimated Extramural HSE Funding Sources The Norwegian Cancer Society Other national grants EU Grants Other international grants
16%
14% 11%
46%
UIO RCN HSE UIO HSE The Norwegian The Norwegian Cancer Cancer SocietySociety Other national grants Other national grants EU Grants Other international grants EU Grants Other international grants
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NCMM-Affiliated Publications 2016 Arenillas, David J.; Forrest, Alistair R.R.; Kawaji, Hideya; Lassmann, Timo; Wasserman, Wyeth W.; Mathelier, Anthony. CAGEd-oPOSSUM: Motif enrichment analysis from CAGE-derived TSSs. Bioinformatics 2016 ;Volum 32.(18) s.2858-2860 OUS UiO Asim, Mohammad; Massie, Charles E.; Orafidiya, Folake; Pértega-Gomes, Nelma; Warren, Anne Yvonne; Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott K.; Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Gregory L.; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Hisham; Stefanos, Niki; Lynch, Andrew G.; Grigorenko, Elena; D’Santos, Clive; Taylor, Christopher; Lamb, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, John R.; Tavaré, Simon; Mills, Ian Geoffrey; McEwan, Iain J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target. Journal of the National Cancer Institute 2016 ; Volum 108 (5)
Overview of the membrane-associated RING-CH (MARCH) E3 ligase family. New Biotechnology 2016 Bjerregaard-Andersen, Kaare; Østensen, Ellen; Scott, John D.; Tasken, Kjetil; Morth, Jens Preben. Malonate in the nucleotide-binding site traps human AKAP18/ in a novel conformational state. Acta Crystallographica. Section F : Structural Biology and Crystallization Communications 2016 ;Volum 72. s.591-597 Chelappa, S; Lieske, N.V; Hagness, M; Line, P.D; Taskén, K; Aandahl, E.M Human regulatory T cells control TCR signalling and susceptibility to suppression in CD4+ T cells. Journal Leukocyte Biology., 100:5-16, In section “Spotlight on Leading Edge Research”, Editorial: Jeschke & Williams. Treg potency and the importance of being fit. Ibid, 1-3. Cieslar-Pobuda, Artur; Rafat, Mehrdad; Knoflach, Viktoria; Skonieczna, Magdalena; Hudecki, Andrzej; Malecki, Andrzej; Urasinska, Elzbieta; Ghavami, Seaid; Los, Marek J. Human induced pluripotent stem cell differentiation and direct transdifferentiation into corneal epithelial-like cells. OncoTarget 2016 ;Volum 7.(27) s.42314-42329 Dukic, Aleksandra; McClymont, David; Tasken, Kjetil. A Cell-Based High-Throughput Assay for Gap Junction Communication Suitable for Assessing Connexin 43-Ezrin Interaction Disruptors Using IncuCyte ZOOM. Journal of Biomolecular Screening 2016
Bains, Simer Jit; Mahic, Milada; Myklebust, Tor Åge; Småstuen, Milada C; Yaqub, Sheraz; Dørum, Liv Marit; Bjørnbeth, Bjørn Atle; Møller, Bjørn; Brudvik, Kristoffer Watten; Tasken, Kjetil. Aspirin as secondary prevention in patients with colorectal cancer: An unselected population-based study. Journal of Clinical Oncology 2016; Volum 34.(21) s.2501-2508 Barfeld, Stefan; Mills, Ian Geoffrey. Mapping Protein-DNA Interactions Using ChIP-exo and Illumina-Based Sequencing. Methods in Molecular Biology 2016 ;Volum 1443. s.119-137 Bauer, Johannes; Bakke, Oddmund; Morth, Jens Preben.
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Engedal, Kim Nikolai; Seglen, Per O.. Autophagy of cytoplasmic bulk cargo does not require LC3. Autophagy 2016 ;Volum 12.(2) s.439-441
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NCMM-AFFILIATED PUBLICATIONS Fiorito, Elisa; Sharma, Yogita; Gilfillan, Siv; Wang, Shixiong; Singh, Sachin Kumar; Somisetty, Venkata Satheesh; Madhumohan, Katika; Urbanucci, Alfonso; Thiede, Bernd; Mills, Ian Geoffrey; Rodriguez, Antoni Hurtado. CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions. Nucleic Acids Research 2016 ;Volum 44. s.10588-10602 Gerner L, Munack S, Temmerman K, Lawrence-Dorner AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG and Morth JP. Data for the co-expression and purification of human recombinant CaMKK2 in complex with calmodulin in Escherichia coli. Data Brief. 2016; 8:733-740. Gerner, Lisa; Munack, Steffi; Temmerman, Koen; Lawrence-Dörner, Ann-Marie; Besir, Huseyin; Wilmanns, Matthias; Jensen, Jan Kristian; Thiede, Bernd; Mills, Ian Geoffrey; Morth, Jens Preben. Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2. Biochemical and Biophysical Research Communications - BBRC 2016 ;Volum 476.(2) s.102-107 Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Cordella, Angela; Campana, Antonella; Hashim, Adnan; Rizza, Pietro; Leggio, Antonella; Gyorffy, Balazs; Simoes, Bruno M; Clarke, Robert B.; Weisz, Alessandro; Catalano, Stefania; Ando, Sebastiano. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. OncoTarget 2016 ;Volum 7.(2) s.1262-1275 Gunasekaran, Stalin Chellappa; Hugenschmidt, Harald; Hagness, Morten; Line, Pål Dag; Labori, Knut Jørgen; Wiedswang, Gro; Tasken, Kjetil; Aandahl, Einar Martin. Regulatory T cells that co-express RORt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Oncoimmunology 2016 ;Volum 5.(4) Gunasekaran, Stalin Chellappa; Lieske, Nora Valeska; Hagness, Morten; Line, Pål Dag; Tasken, Kjetil; Aandahl, Einar Martin. Human regulatory T cells control TCR signaling and susceptibility to suppression in CD4+ T cells. Journal of Leukocyte Biology 2016 ;Volum 100.(1) s.5-16 Halnes, Geir; Mäki-Marttunen, Tuomo; Keller, Daniel; Pettersen, Klas; Andreassen, Ole Andreas; Einevoll, Gaute. Effect of Ionic Diffusion on Extracellular Potentials in Neural Tissue. PloS Computational Biology 2016 ;Volum 12.(11) Hong, Zebin; De Meulemeester, Laura; Jacobi, Annemarie;
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Pedersen,JanSkov; Morth,JensPreben;Andreasen,PeterA.; Jensen, Jan Kristian. Crystal structure of a Two-domain fragment of hepatocyte growth factor activator inhibitor-1. Journal of Biological Chemistry 2016 ;Volum 291.(27) s.14340-14355 Itkonen, Harri; Gorad, Saurabh Sayajirao; Duveau, Damien Y.; Martin, Sara E.S.; Barkovskaya, Anna; Bathen, Tone Frost; Moestue, Siver Andreas; Mills, Ian Geoffrey. Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism. OncoTarget 2016 ;Volum 7.(11) s.12464-12476 Leo, Jack Christoffer; Oberhettinger, Philipp; Yoshimoto, Shogo; Udatha, D.B.R.K. Gupta; Morth, Jens Preben; Schutz, Monika; Hori, Katsutoshi; Linke, Dirk. Secretion of the Intimin passenger domain is driven by protein folding. Journal of Biological Chemistry 2016; Volum 291.(38) s.20096-20112 Leroy, Emilie; Defour, Jean-Philippe; Sato, Takeshi; Dass, Sharmila; Gryshkova, Vitalina; Shwe, Myat; Staerk, Judith; Constantinescu, Stefan N; Smith, Steven O. His499 Regulates Dimerization and Prevents Oncogenic Activation by Asparagine Mutations of the Human Thrombopoietin Receptor. Journal of Biological Chemistry 2016 ;Volum 291.(6) s.2974-2987 Liu, Lisa L.; Landskron, Johannes; Ask, Eivind Heggernes; Enqvist, Monika; Sohlberg, Ebba; Traherne, James A.; Hammer, Quirin; Goodridge, Jodie; Larsson, Stella; Jayaraman, Jyothi; Oei, Vincent Yi Sheng; Schaffer, Marie; Tasken, Kjetil; Ljunggren, Hans-Gustaf; Romagnani, Chiara; Trowsdale, John; Malmberg, Karl-Johan; Béziat, Vivien. Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans. Cell reports 2016 ;Volum 15.(3) s.1088-1099 Lorvik, Kristina Berg; Hammarström, Clara Louise; Fauskanger, Marte; Haabeth, Ole Audun; Zangani, Michael M; Haraldsen, Guttorm; Bogen, Bjarne; Corthay, Alexandre. Adoptive transfer of tumor-specific Th2 cells eradicates tumors by triggering an in situ inflammatory immune response. Cancer Research 2016;Volum 76.(23) s.6864-6876 Lizio, M; Harshbarger, J; Abugessaisa, I; Noguchi, S; Kondo, A; Severin, J; Mungall, C; Arenillas, D; Mathelier, A; Medvedeva, Y.A; Lennartsson, A; Drabløs, F; Ramilowski, JA; Rackham, O; Gough, J; Andersson, R; Sandelin, A; Lenasescu, H; Ono, H. Bono, Y. Hayashizaki, P. Carninci, A.R.R. Forrest, T. Kasukawa* and H. Kawaji*. Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals. Nucleic Acids Research, 2016. doi: 10.1093/nar/gkw995
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NCMM-AFFILIATED PUBLICATIONS Nucleic Acids Research
PRINT ISSN: 0305-1048 ONLINE ISSN: 1362-4962
VOLUME 44
Nucleic Acids Research VOLUME 44
ISSUE 22
2016
https://academic.oup.com/nar
ISSUE 22 2016 PAGES 10527–11033 09/12/16 5:01 PM
McNair, C; Urbanucci, Alfonso; Comstock, CES; Augello, MA; Goodwin, JF; Launchbury, R; Zhao, SG; Schiewer, MJ; Ertel, A; Karnes, J; Davicioni, E; Wang, L; Wang, Q; Mills, Ian Geoffrey; Feng, FY; Li, W; Carroll, JS; Knudsen, KE. Cell cycle-coupled expansion of AR activity promotes cancer progression. Oncogene 2016 (36), 1655–1668; doi:10.1038/onc.2016.334 Munkley, Jennifer; Vodak, Daniel; Livermore, Karen E.; James, Katherine; Wilson, Brian T.; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Harries, Lorna W.; Leung, Hing Y.; Robson, Craig N.; Mills, Ian Geoffrey; Rajan, Prabhakar; Elliott, David J.. Glycosylation is an androgen-regulated process essential for prostate cancer cell viability. EBioMedicine 2016 ;Volum 8. s.103-116 Munkley J, Mills IG and Elliott DJ. The role of glycans in the development and progression of prostate cancer. Nature Reviews Urology. 2016; 13(6):324-333. Rekvig, Ole Petter; Thiyagarajan, Dhivya; Pedersen, Hege Lynum; Horvei, Kjersti Daae; Seredkina, Natalya. Future perspectives on pathogenesis of Lupus Nephritis: facts, problems, and potential causal therapy modalities. American Journal of Pathology 2016 ;Volum 186.(11) s.2772-2782 Ross-Adams, Helen; Ball, Stephen; Lawrenson, Kate; Halim, Silvia; Russell, Roslin; Wells, Claire; Strand, Siri H.; Ørntoft, Torben F.; Larson, Melissa; Armasu, Sebastian; Massie, Charles E.; Asim, Mohammad; Mortensen, Martin M.; Borre, Michael; Woodfine, Kathryn; Warren, Anne Y.; Lamb, Alastair D.; Kay, Jonathan; Whitaker, Hayley; Ramos-Montoya, Antonio; Murrell, Adele; Sørensen, Karina D.; Fridley, Brooke L.; Goode, Ellen L.; Gayther, Simon A.; Masters, John; Neal, David E; Mills, Ian Geoffrey. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. OncoTarget 2016;Volum 7.(46) s.74734-74746 Shaw GL, Whitaker H, Corcoran M, Dunning MJ, Luxton
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H, Kay J, Massie CE, Miller JL, Lamb AD, Ross-Adams H, Russell R, Nelson AW, Eldridge MD, Lynch AG, RamosMontoya A, Mills IG, et al. The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer. European Urology. 2016; 70(2):214-218. Shi, Jianxin; Hua, Xing; Zhu, Bin; Ravichandran, Sarangan; Wang, Mingyi; Nguyen, Cu; Brodie, Seth A; Palleschi, Alessandro; Alloisio, Marco; Pariscenti, Gianluca; Jones, Kristine; Zhou, Weiyin; Bouk, Aaron J; Boland, Joseph; Hicks, Belynda; Risch, Adam; Bennet, Hunter; Luke, Brian T; Song, Lei; Duan, Jubao; Liu, Pengyuan; Kohno, Takashi; Chen, Qingrong; Meerzaman, DAoud; Marconett, Crystal; Laird-Offringa, Ite; Mills, Ian Geoffrey; Caporaso, Neil E; Gail, Mitchell H; Pesatori, Angela Cecilia; Consonni, Dario; Bertazzi, Pier Alberto; Chanock, Stephen J; Landi, Maria Theresa. Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study. PLoS Medicine 2016 ;Volum 13 Shi, Wenqiang; Fornes, Oriol; Mathelier, Anthony; Wasserman, Wyeth W.. Evaluating the impact of single nucleotide variants on transcription factor binding. Nucleic Acids Research 2016 ;Volum 44.(21) s.10106-10116 Stiksrud, Birgitte; Lorvik, Kristina Berg; Kvale, Dag; Mollnes, Tom Eirik; Ueland, Per Magne; Trøseid, Marius; Tasken, Kjetil; Dyrhol- Riise, Anne Ma. Plasma IP-10 is increased in immunological nonresponders and associated with activated regulatory T cells and persisting low CD4 counts. Journal of Acquired Immune Deficiency Syndromes 2016 ;Volum 73.(2) s.138-148 Subramani, Saranya; Perdreau-Dahl, Harmonie; Morth, Jens Preben. The magnesium transporter A is activated by cardiolipin and is highly sensitive to free magnesium in vitro. eLIFE 2016 ;Volum 5.(2016) Tekpli, Xavier; Urbanucci, Alfonso; Hashim, Adnan; Vågbø, Cathrine Broberg; Lyle, Robert; Kringen, Marianne
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NCMM-AFFILIATED PUBLICATIONS K.; Staff, Anne Cathrine; Dybedal, Ingunn; Mills, Ian Geoffrey; Klungland, Arne; Staerk, Judith. Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells. Epigenetics & Chromatin 2016;Volum 9.(1) Tonby, Kristian; Wergeland, Ida; Lieske, Nora Valeska; Kvale, Dag; Tasken, Kjetil; Dyrhol-Riise, Anne Ma. The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection. BMC Infectious Diseases 2016 ;Volum 16:599. s.1-12 Vindedal, Gry Fluge; Thoren, Anna; Jensen, Vidar; Klungland, Arne; Zhang, Yong; Holtzman, Michael; Ottersen, Ole Petter; Nagelhus, Erlend Arnulf. Removal of aquaporin-4 from glial and ependymal membranes causes brain water accumulation. Molecular and Cellular Neuroscience 2016 ;Volum 77. s.47-52 Wehbi, Vanessa Leila; Tasken, Kjetil. Molecular mechanisms for cAMP-mediated immunoregulation in T cells - role of anchored protein kinase a signaling units. Frontiers in Immunology 2016 ;Volum 7:222.
c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks. EBioMedicine. 2017 Chellappa, Stalin; Hugenschmidt, Harald; Hagness, Morten; Subramani, Saranya; Melum, Espen; Line, Pål Dag; Labori, Knut-Jørgen; Wiedswang, Gro; Tasken, Kjetil & Aandahl, Einar Martin CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer. Journal of Immunology, 2017, 198 (4) 1729-1739 Dukic, Aleksandra; Haugen, Linda Hofstad; Pidoux, Guillaume; Leithe, Edward; Bakke, Oddmund & Tasken, Kjetil A protein kinase A-ezrin complex regulates connexin 43 gap junction communication in liver epithelial cells. Cellular Signalling 2017; Volume 32 s 1- 11 Geybels MS, McCloskey KD, Mills IG and Stanford JL. Calcium Channel Blocker Use and Risk of Prostate Cancer by TMPRSS2:ERG Gene Fusion Status. Prostate. 2017; 77(3):282-290. Khan, A; Mathelier, A Intervene: a tool for intersection and visualization of multiple gene or genomic region sets. bioRxiv, 2017. https://doi.org/10.1101/109728 Martin-Martin, R., Portantier, M., Chica-Balaguera, N., Nyquist-Andersen, M., Mata, J., Lopez-Aviles, S. A PP2A-B55-mediated crosstalk between TORC1 and TORC2 regulates the differentiation response in fission yeast. Current Biology, 2017 Jan 23; 27(2):175-188)
Whitington, Thomas; Gao, Ping; Song, Wei; Ross-Adams, Helen; Lamb, Alastair D.; Yang, Yuehong; Svezia, Ilaria; Klevebring, Daniel; Mills, Ian Geoffrey; Karlsson, Robert; Halim, Silvia; Dunning, Mark J.; Egevad, Lars A.; Warren, Anne Yvonne; Neal, David E.; Grönberg, Henrik; Lindberg, Johan; Wei, Gong-Hong; Wiklund, Fredrik. Gene regulatory mechanisms underpinning prostate cancer susceptibility. Nature Genetics 2016 ;Volum 48.(4) s.387-397
NCMM-AFFILIATED PUBLICATIONS AT Q1 2017 Barfeld SJ, Urbanucci A, Itkonen HM, Fazli L, Hicks JL, Thiede B, Rennie PS, Yegnasubramanian S, DeMarzo AM and Mills IG.
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Massie CE, Mills IG and Lynch AG. The importance of DNA methylation in prostate cancer development. Journal of Steroid Biochemistry Mol Biol. 2017; 166:1-15. Ross-Adams H, Lamb AD, Dunning MJ, Halim S, Lindberg J, Massie CM, Egevad LA, Russell R, Ramos-Montoya A, Vowler SL, Sharma NL, Kay J, Whitaker H, Clark J, Hurst R, Gnanapragasam VJ, et al. Corrigendum to “Integration of Copy Number and Transcriptomics Provides Risk Stratification in Prostate Cancer: A Discovery and Validation Cohort Study” [EBioMedicine 2 (9) (2015) 1133-1144]. EBioMedicine. 2017; 17:238 Zuber V, Bettella F, Witoelar A, Consortium P, Cruk G, Consortium B, Consortium T, Andreassen OA, Mills IG and Urbanucci A. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genomics. 2017; 18(1):270.
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Selection of press items from NCMM 2016/Q1 2017 PRESS ITEMS FROM NCMM FOR 2016/Q1 2017 2016
• UiO Faculty of Medicine News, March 2016: Bacteria use their own pumps to collect magnesium, research from NCMM group leader Preben Morth featured: http://www.med.uio.no/english/research/news-andevents/news/2016/bacteria-pumps-collect-magnesium.html • Science Daily, April 2016: Bacteria use their own pumps to collect magnesium: https://www.sciencedaily.com/releases/2016/04/160406100529.htm
NCMM Director, Professor Kjetil Taskén, awarded King Olav V’s Prize for Cancer Research 2016
1. The Norwegian Cancer Society, 9 March 2016: Kong Olavs kreftforskningspris 2016: https:// kreftforeningen.no/aktuelt/siste-nyheter/ kong-olav-vs-kreftforskningspris-2016/ 2. UiO Faculty of Medicine, March 9, 2016: Kjetil Taskén får Kong Olav Vs kreftforskningspris: http:// www.med.uio.no/om/aktuelt/aktuelle-saker/2016/ kjetil-tasken-kreftforskningsprisen.html 3. Oslo Cancer Cluster, March 9, 2016: Kjetil Taskén awarded King Olav V’s Cancer Research Award 2016 - http://occincubator.com/professor-kjetil-tasken-atthe-university-of-oslo-awarded-king-olav-vs-cancerresearch-award-2016/ 4. Forskning.no, March 9, 2016: Kongelig pris til kreftforsker i Oslo: http://forskning.no/kreft-forskningspriser/2016/03/ kongelig-pris-til-kreftforsker-i-oslo 5. OsloBy, March 9, 2016, Kongelig pris til kreftforsker: http://www.osloby.no/nyheter/Kongelig-pris-tilkreftforsker-8387376.html 6. Aftenposten, 10 March 2016, Kongelig pris til kreftforsker (page 6) 7. KG Jebsen Centre for Cancer Immunotherapy, March 10, 2016, Kjetil Taskén Receives King Olav V’s Prize: http://www.med.uio.no/klinmed/english/research/ centres/kgj-cancer-immunotherapy/news-andevents/news/2016/jcit-scientist-kjetil-taskén-recieves-king-olav-vs.html 8. Oslo University Hospital research pages, March 2016: King Olav V’s Cancer Research Prize for 2016 to Kjetil Taskén: http://www.ous-research.no/home/ous/news/15957 9. UiO, Faculty of Science and Mathematics, March 11, 2016, Kong Olav V’s kreftforskningspris til Kjetil Taskén: https://titan.uio.no/node/1404 10. Norwegian Inflammation Network, NORIN, March 11, 2016, NORIN congratulates Kjetil Taskén on receiving King Olav V Prize for Cancer Research: http://
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norinnetwork.no/blog/norin-congratulates-kjetiltask%C3%A9n-receiving-king-olav-v-price-cancer-research-2016 • NRK Radio P2, Ekko, March 10, 2016, Interview with Anne Synnevåg about New data and development on stress and cancer spread through the lymphatic system: https://radio.nrk.no/direkte/p2#start=10:04:42 • Dagbladet, 23 March 2016: En revolusjon i kreftbehandlingen: http://redir.opoint.com/?key=7ABntAryxnmi nBHcOx8M
VG, 31 May 2016: «Pille til 80 øre kan redde 1 av 5 tarmkreftpasienter»:
http://www.vg.no/nyheter/innenriks/helse-og-medisin/ pille-til-80-oere-kan-redde-1-av-5-tarmkreftpasienter/a/23698641/ June 2016: Kveldsnytt – Interview with Kjetil Taskén about paper in Journal of Clinical Oncology United Press International (UPI), 2 June 2016, Low dose of aspirin tied to longer colon cancer survival: http://www. upi.com/Health_News/2016/06/02/Low-dose-aspirintied-to-longer-colon-cancer-survival/6511464896717/
6 June 2016: Presentation of the King Olav V’s Prize for Cancer Research:
1. Included on TV2 News 2. Konghuset: http://www.kongehuset.no/nyhet.html?tid=136269 &sek=26939 3. Budstikka: http://www.budstikka.no/kreft/kjetil-task -n/jar/kjetil-task-n-mottok-prestisjetung-pris-for-kreftforskning/s/5-55-324452 4. Kreftforeningen, Kreft forskning pris vinner: https:// kreftforeningen.no/aktuelt/siste-nyheter/kreftforskningsprisvinner-med-oppsiktsvekkende-studie/ 5. Kong Olavs Kreftforskningsprisen 2016: https://kreftforeningen.no/forskning/kong-olav-vskreftforskningspris/kreftforskningsprisen-2016/ • NRK radio interview with Kjetil Taskén, in connection with a specialist meeting about immunotherapy in Hamar, 28 September 2016 (NRK Hedmark og Oppland) • Oppslag i Oppland Arbeiderblad, 28 September 2016, news about Kjetil Tasken and meeting about immunotherapy in Hamar. • Budstikka: Asker og Bærums Budstikke, 29 October 2016, Ni kreftforskere får 53 mill: – Vi er takknemlige: http:// www.budstikka.no/institutt-for-kreftforskning/kreftstudie/forskning/ni-kreftforskere-far-53-mill-vi-er-takknemlige/s/5-55-388830
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SELECTION OF PRESS ITEMS FROM NCMM 2016/Q1 2017
Selection of press items from NCMM 2016/Q1 2017
2017
• Titan.uio.no, 9 February 2017: Leter etter snarvei i den individtilpassede kreftbehandlingen: https://titan.uio.no/ node/2146 • Dagens Medisin, 16 February 2017: Kan føre til at vi må omdefinere evidensbasert medisin (Feature on presentation given by Kjetil Taskén at Oslo Life Science Conference): https://www.dagensmedisin.no/artikler/ 2017/02/16/-kan-fore-til-at-vi-ma-omdefinere-evidensbasert-medisin/
Professor Per Seglen awarded King Olav V’s Prize for Cancer Research
1. Dagens Medisin, 6 March 2017, UiO professor hedres med prestisjes pris for kreftforskning: https://www. dagensmedisin.no/artikler/2017/03/06/uio-professor-hedres-med-prestisjepris-for-kreftforskning/ 2. Kreftforeningen, 6 March 2017, Kong Olav Vs kreftforskningspris: https://kreftforeningen.no/aktuelt/sistenyheter/kong-olav-vs-kreftforskningspris-2017/ 3. Fordbladet, 6 March 2017, Kong Olav Vs kreftforskningspris: http://www.fjordabladet.no/npk/innenriks/
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2017/03/06/Per-Ottar-Segel-f%C3%A5r-Kong-Olav-Vskreftforskingspris-14399587.ece 4. Oslo University Hospital, King Olav V’s Prize for Cancer Research: http://www.ous-research.no/home/ institute/news/17011 5. Budstikka, 13 March, Bærumsforsker får kreftforskningspris: https://www.budstikka.no/kreftforeningen/ kreft/forskning/barumsforsker-far-kreftforskningspris/s/5-55-450691 6. Titan.uio.no, 16 March, Kong Olav Vs kreftforskningspris til Per Ottar Seglen: https://titan.uio.no/node/2222
Publication of NCMM co-authored report into digital biotechnology in Norway
1. Titan.uio.no, 21 March, Digital bioteknologi = raskere utvikling + lavere pris: https://titan.uio.no/node/2241 2. Dagens Medisin, 22. March 2017, Digitalisering gir færre utfordringer med innovasjon: https://www.dagensmedisin.no/artikler/2017/03/22/digitalt-orienterte-bioteknologibedrifter-har-farre-innovasjonsutfordringer/
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Core Facilities at NCMM
NCMM hosts several core facilities that are all open for use by researchers from outside the Centre. Core facilities at NCMM include:
HIGH-THROUGHPUT CHEMICAL BIOLOGY SCREENING PLATFORM The platform supports the discovery of small molecules to probe, explore and modulate biological systems.
Services
• High-throughput screening of small molecules. Projects can use our in-house libraries (total of 68,000 compounds) or those supplied by the customers themselves • Assay development assistance • Data management
Technologies
• Detection Platforms — PerkinElmer EnVision® Multilabel Plate Reader — Molecular Devices FLIPR384 Fluorometric Imaging Plate Reader — BD LSR Fortessa HTS flow cytometer — BioTek Synergy™ Neo2 MultiMode Microplate Reader — IntelliCyt iQue Screener PLUS
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• Liquid Handling — Hamilton Microlab Star — Echo 550 connected to a fully automated workstation (Labcyte Access) — BioTek MultiFlo FX dispenser/ washer — Thermo Fisher Scientific Cytomat Cell Incubator — Brooks FluidX® XPeel® Automated Microplate DeSealer
Informatics
Other Instrumentation
For file transfer, encrypted VPN access is provided to the facility’s secure server.
• PerkinElmer FlexDrop Exi dispenser • Agilent PlateLoc Thermal Microplate Sealer • BenchCel Microplate Handling Workstation • Eppendorf microtitre plate centrifuge • Barcode printing and reading • Biotek EL406 plate washer and dispenser workstation • Roylan StoragePod
With the facility’s dotmatics database system the CB Platform can provide results in our standard format or one customised for your own set-up. Even if you don’t have your own database, one can be provided to you with remote access to the Dotmatics server allowing you to query and analyse your own results.
Contact persons:
Johannes Landskron (Platform manager) and Paul Ragnar Berg (Head Engineer)
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ZEBRAFISH CORE FACILITY NCMM has both tanks for keeping zebrafish, and separate tanks for generating/regenerating fish lines. The facility also has tanks for breeding, three iSPAWN for large scale production of synchronized eggs, and nets.
Key personnel at the core facilities. From left: Daniel James Wrobleski, Eirin Solberg, Ola Rumohr Blingsmo, Johannes Landskron, Paul Ragnar Berg, and Rønnaug Steen Kolve.
PEPTIDE ARRAY CORE FACILITY Equipment is available for: • Microinjection • Behavioural tracking and chemical screening: • Larvae manipulation and imaging • To come: EEG
Services offered at NCMM
The facility’s personnel have experience within aqua culture, fish health, screening and characterisation of new lines, GMO, 360° live-imaging of larvae, chemical screening, behavioural tracking, and microinjection (automatic/manual).
Contact:
• Synthesis of peptide arrays on cellulose membranes • Synthesis of lyophilized peptides • Amino acid analysis of peptide hydrolysates Ola Rumohr Blingsmo, Senior Engineer Check the NCMM Core Facilities web pages for more detailed information about our core facilities.
Users can use the facility to do their research, or they can buy services and analyses.
Contact:
Rønnaug Steen Kolve, Head Engineer
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Personnel at NCMM DIRECTOR AND ADMINISTRATION Director
Kjetil Taskén
(from June 2016)
(Core Facility Leader) Rønnaug Kolve Steen (Head Engineer)
PhD Fellows
Saranya Subramani (until May 2016) Theis Sommer (until June 2016) Julia Weikum (from April 2017)
Senior Engineers
Chief Administrative Officer
Eshrat Babaie Gladys Tjørhom
Acting Chief Administrative Officer/ Head of Office
RESEARCH GROUPS: PROSTATE CANCER GROUP
Ingrid Kjelsvik (on leave)
Elisa Bjørgo
Acting Deputy Head of Office Siri Høgseth
Financial Officers
MSc Student
NCMM Group Leader
Stefanie Ruhland (Erasmus Student, April 2016 – July 2016 Annika Kratzel (Erasmus Student, April 2017 - July 2017)
SIGNALLING NETWORKS IN HEALTH AND DISEASE
Ian Mills (until June 2016)
Head Engineers
Mette Kvernland Anita Skolem
Ingrid Jenny Guldvik (until June 2016) Frank Sætre (until July 2016)
NCMM Group Leader
Human Resources Officer
Senior Researcher Nikolai H. Engedal
Marianne Enger Martine Schrøder
Communications Officer
Guest Researcher
Senior Researchers
Higher Executive Officer
Postdoctoral Fellows
Postdoctoral Fellows
Nina Modahl
Annabel Darby (from January 2017) Carlos Romeo Rodriguez
IT Team
George Magklaras (Head of IT) Gang Cheng Melaku Tadesse
LABORATORY OPERATIONS AND CORE FACILITIES HSE Coordinator
Liv E. Alver Bjørland
Chemical Biology Platform
Johannes Landskron (Platform Manager) Paul Ragnar Berg (Head Engineer) Eirin Solberg (Principal Engineer)
Peptide Synthesis Service Ola Rumohr Blingsmo
Zebrafish Core Facility Camila V. Esguerra
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Per O. Seglen
PhD Fellows
Lisa Gerner (until February 2017) Morten Luhr Bertrand Simon - Joint PhD student at EMBL Hamburg (until March 2017) Paula Szalai
MEMBRANE TRANSPORT GROUP Jens Preben Morth Principal Engineer Bojana Sredic
Postdoctoral Fellows
Johannes Bauer Harmonie Perdreau-Dahl Saranya Subramani
Scientific Officers
Einar Martin Aandahl
Harri Itkonen Alfonso Urbanucci
NCMM Group Leader
Kjetil Taskén
Theresa Ahrens (from July 2016, joint with Staerk group) Simer Jit Bains (NCMM affiliate) Deepak Balaji Thimiri Govinda Raj Ana I. Costa Calejo Stalin Chelappa (from July 2016) Dinh-Toi Chu Andrea Cremaschi (from October 2016) Aleksandra Dukic (from January 2017) Kushi Kushekar Anna-Mari Lone Kristina B. Lorvik Maria-Niki Mylonakou (until May 2016) Vanessa L Wehbi (until January 2017)
PhD Fellows
Simer Jit Bains (until January 2016) Stalin Chelappa (until June 2016) Aleksandra Dukic (until December 2016) Nora V. Lieske (until June 2016)
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PERSONNEL AT NCMM
Ellen Østensen
MSc Students
Marthe Jøntvedt Jørgensen Johanne Hermansen Uthus
Administrative Officer
PhD Fellows
Julia-Kristina Madsen-Østerbye Oksana Svärd
Berit Barkley
COMPUTATIONAL BIOLOGY AND GENE REGULATION
BREAST CANCER GROUP
NCMM Group Leader
NCMM Group Leader
Postdoctoral Fellow
Head Engineer
PhD Fellow
Antoni Hurtado Siv Gilfillan
Postdoctoral Fellows
Anne Marthe Fosdahl (from September 2016) Venkata S. Somisetty (until January 2017) Sachin Kumar Singh
PhD Fellow
Anthony Mathelier (from May 2016) Aziz Khan (from October 2016) Marius Gheorghe (from September 2016)
MSc Student
MSc Student
Mari Nyquist-Andersen
Signe H. Kaarstad (until February 2017)
STEM CELL GROUP NCMM Group Leader Judith Staerk
Principal Engineer Kirsti E. Præsteng
Postdoctoral Fellows
Theresa Ahrens (from July 2016, joint with Taskén Group) Safak Caglayan Artur Cieslar-Pobuda Adnan Hashim Ida Jonson (until October 2016) Marie Rogne
Nikolina Sekulic
Principal Engineer
Stine Malene Hansen Wøien
Senior Researcher Dario Segura-Pena
BIONANOTECHNOLOGY AND MEMBRANE SYSTEMS NCMM Group Leader
Irep Gözen (from September 2016)
CELL CYCLE REGULATIONS NCMM Group Leader
Assistant
NCMM Group Leader
Eleftherios Pavlos (Erasmus student, October 2016- March 2017)
Elisa Fiorito (until May 2016) Shixiong Wang Neus Daviu (Erasmus student, September 2016 - April 2017)
STRUCTURAL BIOLOGY AND CHROMATIN
Sandra Lopez-Aviles
Head Engineer
Postdoctoral Fellows
Nathalia Chica-Balaguera Ruth Martîn Martîn Marina Portantier
CHEMICAL NEUROSCIENCE NCMM Group Leader
Camila Vicencio Esguerra
Head Engineer
Rønnaug Steen Kolve
Postdoctoral Fellows
David Ramonet-Jimenez (from September 2016) Ettore Tiraboschi
Research Technician
Daniel James Wrobleski
MSc Students
THE ADMINISTRATION TEAM AT NCMM NCMM benefits from the support of a full administrative team that provides service to the Centre’s research groups. The team is led by acting CAO, Elisa Bjørgo. All administrative and support functions, including laboratory operations and core facilities, finance, HR, research administration, IT, and communications are carried out in-house by the Centre’s dedicated administration department. With the merging of NCMM and BiO, administration-related staff now number 18 full-time employees; including engineers working at our core facilities.
Gezime Seferi (from February 2017) Anna Thao Nguyen (from August 2016)
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NCMM International staff distribution FINLAND
2%
POLAND
2%
DENMARK
5%
GERMANY
CHINA
15%
3%
ROMANIA
2%
UKRAINE
UK UK
2%
1% 3% FRANCE
PAKISTAN IRAN
2%
3%
CROATIA
5%
2%
USA
5% TURKEY
3%
PORTUGAL
EL SALVADOR
3%
2%
GREECE
2%
INDIA
10%
3%
5%
COLOMBIA
2%
VIETNAM ETIOPIA
SPAIN
8%
SERBIA
3%
ITALY
7%
KOSOVO
2%
ARGENTINA
2%
1% Director
8%
4%
10% 6%
3%
63%
NCMM international staff
8%
37%
Type of 61% employment
17%
Norway
Group leaders
30%
International
13%
Senior researchers Director Postdocs Group Leaders Senior Researchers PhD fellows 39% Postdocs PhD Engineers fellows Engineers Administration Administration IT IT Students Students Other personell Other personell
The overview represents the merged NCMM in the beginning of 2017.
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Personnel statistics
NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS
Number of employees 100
80
60
40
20 NCMM Staff (incl. FP) NCMM Staff (excl. FP)
0 2010
2011
2012
2013
2014
The staff was reduced in 2015 and 2016 due to rotation of two research groups out of the centre. In addition, the Founding Partner (FP) arrangement was terminated in 2015. In 2016, one new research group rotated in and this group will grow in size in the coming years. Furthermore, a second group leader/assistant director has recently been recruited and will start in the fall 2017.
All Staff
61% 61%
Gender Balance 39% 39%
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2015
2016
2017
Numbers for 2017 are estimated and represents the Centre after the merger. The newly merged NCMM has in total 3 research groups recruited in 2016. In addition, the Centre is planning to recruit two more groups in 2017/2018. We therefore expect to see an increase in staff the next couple of years.
Group leaders
Gender
56% 56% Balance
44% 44%
Female Male
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Grafisk design: Millimeterpress Trykk: Rolf Ottesen Foto: Millimeterpress
http://www.med.uio.no/ncmm/english/ P.O.Box 1137 Blindern, NO-0318 Oslo, Norway Forskningsparken, Gaustadalleen 21, 0349 Oslo, Norway
NCMM CO-FUNDERS
NORDIC EMBL PARTNERSHIP FOR MOLECULAR MEDICINE
NORDIC EMBL PARTNERSHIP FOR MOLECULAR MEDICINE
INTERNATIONAL COLLABORATIONS INCLUDE