Final Report Summary - MADCIN (Defining the Impact of Chromosome Instability in Tumor Initiation, Maintenance and Relapse)
Chromosome instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a principal contributor to genetic heterogeneity in cancer as well therapeutic resistance. Overexpression of the mitotic checkpoint protein Mad2, is a common event seen in many human cancers and leads to CIN and the development of aneuploid tumors in mouse models. However, recent observations from various laboratories suggest that aneuploidy can promote or suppress tumorigenesis depending on the context or the pre-existing levels of aneuploidy. This proposal aims to understand the relationship between aneuploidy and tumor formation and to identify in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor. We have generated several inducible mouse models that recapitulate the aneuploidy state of human tumors, to investigate the role of CIN in promoting or suppressing cancer. We were able to show that while Mad2 induces aneuploid tumors in vivo and cooperates with oncogenic Kras in lung tumorigenesis, its overexpression is detrimental in breast tumorigenesis. Moreover, we had shown that CIN facilitates escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and that this CIN could be responsible for tumor relapse after targeted therapies in a model of Kras induced lung cancer. We have now shown that despite the detrimental effect of Mad2 overexpression in breast cancer, it also facilitates the development of resistant subclones in these models. We have used an innovative three-dimensional in vitro culture system to isolate and characterize tumor cells responsible for relapse.