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Dissecting the Role of Chromosome Instability in Cancer

Final Report Summary - CINCANCER (Dissecting the Role of Chromosome Instability in Cancer)

Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, 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.
This proposal is aiming 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 inducible mouse models that recapitulate the aneuploidy state of human tumors, to investigate the role of CIN in promoting or suppressing cancer. Preliminary results show that while Mad2 induces aneuploid tumors in vivo and cooperates with oncogenic Kras in lung tumorigenesis, its overexpression is detrimental in breast tumorigenesis.
In addition, 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. Recent data from our laboratory suggests that despite the detrimental effect of Mad2 overexpression in breast cancer, it also facilitates relapse in these models.
Therefore, we are investigating how CIN potentiates oncogene independence. It is possible that some CIN cells in the primary tumor are already independent of the initiating oncogene prior to treatment. Alternatively, CIN cells are more susceptible of acquiring additional mutations and evolve to become independent of the initiating lesion.