Causes and Consequences of Whole Genome Duplication in Cancer Progression and Acquired Drug Resistance

Summary Recent studies show that whole genome duplication (WGD) is a frequent event in cancer evolution that promotes chromosomal instability and aneuploidy. WGD tumors have worse prognosis, elevated drug resistance, and increased metastatic potential when compared with near-diploid counterparts. However, the mechanisms driving

WGD during cancer evolution remain unclear. This is because the events that lead to WGD occur asynchronously and at low frequency, making them difficult to capture using traditional approaches such as fixed endpoint approaches. My lab has pioneered genetically encoded biosensors and image analysis techniques to biochemically

characterize thousands of individual cells for multiple days as they go through normal or aberrant cell cycles. Using these approaches, we have found that WGD occurs in response to common stress conditions such as osmotic stress, DNA damage, and ribosome collisions. This process involves two steps: first cells go from G2 to

G0 without entering into mitosis (i.e. mitotic bypass). Second, some cells escape cell cycle arrest and enter S- phase, thereby re-duplicating their genome. Furthermore, our data show that DNA damage caused by commonly used chemotherapeutics promotes WGD in cancer cells raising questions about the role of chemotherapy-

induced WGD in acquired drug resistance. This is particularly important in metastatic Triple Negative Breast Cancer (mTNBC), for which DNA damaging agents are still a mainstream treatment, and the development of resistance continues to be a devastating health care problem (median survival rate