Chromosomal instability in tumorigenesis: The importance of how much, where and when

Abstract

Chromosomal instability (CIN) is at the heart of genome destabilisation, but so far, many questions about its role in tumorigenesis remained unanswered. This was partly due to technical limitations and difficulties to accurately study the effects of CIN in organisms. Here we present a novel mouse model for CIN in which various levels of CIN can be induced in a time and tissue specific manner. In chapter 2 we describe that a specific level of CIN causes early onset tumorigenesis in the small intestine. In the tumour prone ApcMin/+ background, moderate CIN caused increased tumorigenesis in both small intestine and colon, but high CIN had this effect only in colon. Finally, we confirmed that loss of heterozygosity (LOH) of the Apc gene is not caused by whole chromosome 18 loss. Most likely, double non-disjunction events or somatic recombination lead to the presence of two mutant alleles and either of these processes can be induced by CIN. Our follow-up experiments described in appendix of chapter 2 showed that CIN had little effect on tumorigenesis when induced at tumour onset or after tumour establishment in ApcMin/+ mice. The impact of CIN on intestinal tumorigenesis thus dependent on the level, site and timing of CIN induction. The CiMKi alleles can be induced in any tissue, making it an attractive model to study CIN in specific tissues, and tumour types and stages. In chapter 3 we show that in a DMBA/TPA-induced skin tumorigenesis model, tumour free survival was decreased in moderate to very high CIN mice. Also, tumour numbers were increased in low to moderate CIN mice, revealing distinct effects of the various CIN levels on skin tumorigenesis. Induction of moderate to high CIN in skin tumours caused rapid regression of the tumours (followed by relapse), confirming that sufficiently high CIN levels can indeed kill tumour cells. Analyses of induced CiMKi expression suggested that tumour initiation and growth is influenced by both cell intrinsic and cell extrinsic factors. Since CIN and aneuploidy are unique features of tumour cells and high CIN is lethal to cells, it has been proposed that aggravating CIN could be a treatment strategy and/or that CIN levels in tumours could be used to predict treatment response. In chapter 4 we performed a small drug library screen and revealed the potential of finding synergistic actions between CIN and taxanes in mouse intestinal adenoma organoids, but also high-light the challenges in using CIN levels as a predictor of killing potential of anti-cancer drugs in human tumour cultures.