Specific regions in the chromosome are commonly lost in the development and progression of cancer, yet much remains to be learned about the role of these deletions in the disease. Researchers in the DelCancer project are using gene editing techniques and experimental models of cell transformation to shine new light on the development and progression of breast cancer, as Dr Anna Sablina explains
Understanding the impact of chromosomal deletions The loss of
DNA in the genome is a common feature of the development and progression of cancer. While alterations and changes to some regions of the genome are thought to play a role in tumourgenic transformation, much remains to be learned about the loss of heterozygosity that is commonly observed in cancer genomes, an area that forms the primary research focus for the ERC-backed DelCancer project. “The main goal of the project is to investigate the consequences to patients of large-scale chromosomal deletions,” says Dr Anna Sablina. This is not an easy question to study, as typically multiple genes are lost simultaneously when large areas of chromosome are deleted. “Some of those genes can suppress the proliferation of cancer cells, but others can confer a selective growth advantage. That’s why it’s really difficult to define the role of these large-scale deletions in the development of cancer,” explains Dr Sablina.
Genetic engineering tools The development of sophisticated new genetic engineering tools is an important step forward in these terms. The project is using both TALEN and CRISPR technologies, which allow researchers to cut DNA at specific locations and manipulate the genome of human cells. “We can mimic the situations that we can
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see in cancer patients. So we can introduce the same large-scale deletions that we see in cancer patients, then assess the role of these deletions on cancer development and progression,” outlines Dr Sablina. Researchers are working mainly with patient cells derived from mammaplasty procedures, and genetically engineering these cells to model the alterations associated with cancer. “We use the TALEN or CRISPR gene-editing techniques
project is using experimental models of cell transformation to investigate the impact of deleting specific chromosomal regions. “We introduce these chromosomal alterations into the model, then we try to figure out what is going on in the cells by looking for different assays and different pathways,” explains Dr Sablina. “We look at whether these large-scale chromosomal deletions can lead to the formation of cancer.”
We can mimic
the chromosomal abnormalities that we can see in cancer patients. These model systems allow us to assess the role of these deletions on cancer development and progression to introduce the genetic alterations that we commonly see in breast cancer patients,” continues Dr Sablina. Researchers are deleting an entire region of the chromosome, rather than a smaller area or specific parts of the chromosome, aiming to establish a protocol for editing the genome on a large scale. The goal then for Dr Sablina and her colleagues is to assess how disrupting the chromosomal network in this way affects cells. “If we have such a large-scale chromosomal deletion, how will it affect gene expression? And will this contribute to cell transformation?” she outlines. The
This research relates to both the early stages of cancer development and its later progression. Some chromosomal alterations may occur at an early stage of cancer development, while others may take place later, an issue which Dr Sablina and her colleagues are investigating. “First of all, we are looking at the cancer genomes. We aim to figure out which alterations recur, to define the border of the deletions, and to define whether the specific deletion is an early event or a late event,” she says. Data from the cell models can also lead to new insights into the molecular mechanisms behind cancer
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