Chromosomal instability (CIN) is a process whereby (parts of) chromosomes are distributed unequally between daughter cells after division. Chromosomes carry genetic information and therefore it is important that every cell has the right set to function properly. Although CIN is a common phenomenon in tumor cells, its role in tumor development is not precisely known.
This thesis focusses on whether and how CIN contributes to tumor development. For this, we developed a mouse model in which different levels of CIN can be induced in specific organs, at the moment of choice. I describe that the level, the location and the moment of CIN induction are important for the effect of CIN. In mouse models that develop intestinal or skin tumors, moderate to high CIN leads to more colon and larger skin tumors. Moderate (not high) CIN also causes more small-intestine tumors and more skin tumors in these tumor-prone models, and spontaneous tumor formation in the small intestine of healthy mice. CIN induction in tumors has little effect on intestinal tumors, while moderate to very high CIN causes regression of skin tumors.
Since high levels of CIN leads to cell death, induction of CIN could potentially enhance the effect of anti-tumor therapies, and the CIN level of tumors could also be predictive of therapy success. Screening of intestinal organoids with various CIN levels shows potential for synergistic use of CIN-increasing compounds, but does not provide a definitive answer about the use of CIN levels to predict therapy outcome.