Impact of the cancer endocycle on cell survival after therapy*

We characterized nuclear morphology and function as cancer cells underwent chemotherapeutic treatment and recovery to identify the unique characteristics that are associated with treatment resistance and successful survival. We found that one way cancer cells can survive systemic therapy is to enter the polyaneuploid cancer cell (PACC) state, a recently-described mechanism of therapy resistance. Cancer cells in this state are physically enlarged, undergo whole-genome doubling resulting in polyaneuploid genomes, and are associated with worse prognosis in cancer patients.  The PACC state is accessed when a cancer cell experiences external stress, such as genotoxic chemotherapy; after a period of recovery, cells exit the PACC state and resume proliferation to repopulate the tumor cell pool. We discovered that cells that survive after therapy are predominantly mononucleated and have increasing nuclear size, enabled by continuous endocycling.  We further found that cells in the PACC state are likely to employ more efficient DNA damage repair. Lastly, while many cancer cells treated with a genotoxic agent succumb to apoptosis shortly after treatment, our data suggest that surviving cancer cells must strike a balance of autophagy to restore cellular homeostasis while avoiding autophagic cell death. Overall, our findings demonstrate the fate of cancer cells following chemotherapy treatment and define key characteristics of the resistant PACC state that is accessed via endocycling. This work is essential for understanding and, ultimately, targeting, cancer resistance and recurrence.