Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a distinct feature of cancer. Recent years have seen conceptual, methodological and technical advances in the field of cancer aneuploidy research, but we are just beginning to scratch the surface of the underlying biology, and the potential vulnerabilities of aneuploid cancer cells remain under-explored. Cancer aneuploidy is therefore a biological enigma and a missed opportunity for cancer therapy.
In order to properly use cancer models in aneuploidy research, we must understand how faithful their aneuploidy landscapes are to those of their tumors-of-origin, and dissect their heterogeneity and stability throughout model propagation. We have recently studied the aneuploidy landscapes of major cancer models: GEMMs, PDXs and cancer cell lines. In the first part of my talk, I will describe the main conclusions of these studies, and highlight important themes emerging from their synthesis.
In the second part of my talk, I will describe our work to identify aneuploidy-induced cellular vulnerabilities (Cohen-Sharir et al. Nature, in press). We have recently mapped the aneuploidy landscapes of ~1,000 human cancer cell lines, analyzed genetic and chemical perturbation screens, and identified an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC). Surprisingly, we also found aneuploid cancer cells to be less sensitive to short-term exposures to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing in the presence of SAC inhibitors, resulting in more mitotic defects and in unstable karyotypes. A specific mitotic kinesin, KIF18A, was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored their sensitivity to SAC inhibition. Our results therefore reveal a novel synthetic lethal interaction between aneuploidy and the SAC, with relevance for the clinical application of SAC inhibitors.