How do forces affect cell behaviour? Mechanical forces greatly influence the behaviour of cells, for example in determining whether they differentiate, proliferate, or adopt a malignant phenotype. Understanding how mechanical forces are transmitted in cells could open up interesting new therapeutic avenues, as Pere Roca-Cusachs of the Mechano-Control project explains. The cells inside our body continuously exert mechanical forces on each other and the scaffold of fibres that surround them, the extra-cellular matrix. Cells are linked to the extra-cellular matrix through molecules called integrins, while another type of molecule called cadherins binds cells to each other. “Whenever forces are applied – either between one cell and the next, or between one cell and the matrix – these and other molecules are subjected to force,” says Pere Roca-Cusachs, the coordinator of the Mechano-Control project. The balance between the forces exerted on integrins and cadherins, and the collective action of these bonds, has a major influence on the behaviour of cells. “It may affect whether a cell proliferates or differentiates into a certain type of cell, or whether it adopts a malignant phenotype,” outlines Roca-Cusachs.
Invasion of tumoroid cells in 3D. In yellow intermediate filaments and magenta actin. Scale bar : 20um
Researchers are also looking at how cells respond to forces in more complex situations, such as in an epithelial or endothelial mono-
Whenever forces are applied – either between one cell and the next, or between one cell and the matrix – integrins and cadherins are subjected to force. Mechano-Control project This issue is central to the work of the Mechano-Control project, a multi-disciplinary project which brings together researchers from across Europe. Researchers in the project are investigating how cells transmit and detect forces, with Roca-Cusachs and his colleagues developing methods to monitor cellular behaviour at different scales, which could lead to new insights into how diseases progress. “On one level, we isolate cells and look at them one-by-one,” he says. Cells don’t exist on their own in tissues, yet researchers can still gain important insights from this work. “What happens if we change the composition of the extra-cellular matrix to look more like cancer? What changes?” asks Roca-Cusachs. “We are developing mimics of this matrix, where we can dynamically change their properties. We can make the matrix get stiffer or softer by applying different kinds of light.”
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layer, as well as in 3-dimensional environments, which are more representative of how a tumour grows in vivo. One part of the project involves understanding how mechanical force is being transmitted to the nucleus of a cell and activating gene transcription. “We’re developing tools to monitor that so that we know when it’s happening,” says Roca-Cusachs. This research could hold important implications for the diagnosis and treatment of certain diseases, such as breast cancer. One current technique to screen for breast cancer is by palpating the breast and looking for hard lumps. “Breast cancer tissue is stiffer than normal tissue, and it is well-known that mechanical forces affect this,” outlines RocaCusachs. Understanding this process and the scales at which it occurs could open up exciting possibilities in developing new therapies or diagnostic tools, something Roca-Cusachs is exploring. “A molecule has been identified
MechanoControl Summer School, September 2019.
that unfolds when a force is exerted, which exposes a domain that was previously hidden. This triggers a biochemical cascade which eventually leads to defects and breast cancer progression,” he explains. “We are looking into drugs to block these interactions.” A lot of progress has been made in this respect, and some drug candidates have been identified, which researchers are now looking to test. These drugs would be designed to essentially fool cells into believing they’re not in an abnormally stiff tissue. “Cells change their behaviour when they are in a stiff place; they further stiffen the tissue by secreting more matrix. If you convince the cells that they’re not in a stiff place, then they will stop secreting this, and this may help restore the normal stiffness of the tissue,” says Roca-Cusachs.
MECHANO-CONTROL Mechanical control of biological function Funded under H2020-FETPROACT-2016-2017 (FET Proactive – Boosting emerging technologies): FETPROACT-01-2016 (grant agreement No. 731957, MECHANO-CONTROL) Partners: King’s College London (KCL), INMLeibniz Institute for New Materials, University Medical Center Utrecht (UMCU), Universitat Politècnica de Catalunya (UPC) and Noviocell BV. Clara Civit, Events and Communications Officer Institute for Bioengineering of Catalonia (IBEC) : @Mechanocontrol E: ccivit@ibecbarcelona.eu W: https://mechanocontrol.eu
Pere Roca-Cusachs is currently Associate Professor at the University of Barcelona, and Group Leader at the Institute for Bioengineering of Catalonia (IBEC). He is also an EMBO Member. His group studies the physical and molecular mechanisms by which cells detect and respond to mechanical signals. In 2019 he received the Young Investigator Award of the European Biophysical Societies Association (EBSA).
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