| Project Detail |
Chromosomal instability and cancer immunity
Cancer cells often display chromosomal instability (CIN) which is associated with the accumulation of losses, gains and rearrangements of DNA. Another hallmark of cancer is immune evasion. Understanding the link between the two and how CIN may affect tumour immune evasion is central for designing effective anti-cancer therapies. Funded by the Marie Sklodowska-Curie Actions programme, the CRISPRCINIMM project will investigate which genes are responsible for altering the immunogenic responses against cancer cells. Researchers will employ gene editing and next generation sequencing technologies to identify the genes in the interferon-inflammatory pathway that drive cancer evolution and impede anti-cancer immunity.
Chromosomal instability (CIN) and the resulting aneuploidies can fuel the dramatic karyotype changes characteristic of tumorigenesis, helping tumors to alter the expression of immune checkpoints and evolving phenotypes related to immune evasion or stimulation. Anti-tumor immunity appears to be dependent on the type and origin of the tumor, while immune evasion has become an obstacle to designing effective anticancer therapeutics. Understanding when CIN promotes or suppress anti-tumor immunity is therefore needed.
However, the mechanism and initiators by which this adjustment occurs and the role that aneuploidy, CIN or specific karyotypes have in this transition are still in the dark.
In order to understand how CIN drives tumor evolution, we need to know how CIN guide cells into different immunogenic responses. Identifying the genes that adjust the role of CIN and aneuploidy in immune evasion can therefore help us unravel the origins of malignant growth and in the future develop more appropriate therapeutic approaches.
My project plan is set to find the genes that trigger and connect chromosome missegregation to the interferon-inflammatory response in cells suffering from CIN using an unbiased genome-wide CRISPR KO screen coupled to a suicide gene switch in human fibroblasts. The use of a suicide gene switch, normally used for cell-based therapy, allows separation of cells that have lost the inflammatory pathway while the screen, along with a next generation sequencing, will find the genes related to that loss. This screen will serve as a base to understand what underlies cancer immune evasion in chromosomally unstable cells. |
