Nuclear morphology predicts cell survival to cisplatin chemotherapy

Abstract

The polyaneuploid cancer cell (PACC) state represents a recently-described paradigm in the study of therapy resistance. Cancer cells in this state are physically enlarged, acquire polyaneuploid genomes resulting from whole-genome doubling, and have been shown to be present in metastatic prostate cancer lesions as well as in the tumors of a variety of cancer types. Initiation of the PACC state begins when a cancer cell experiences a stressor, such as a genotoxic chemotherapy, and ends after a period of recovery following the release of the treatment cells exit the PACC state and resume proliferation to repopulate the tumor cell pool. One notable characteristic of cancer cells in the PACC state is their distinctive nuclear morphologies. Evidence in the literature demonstrates that abnormal nuclear morphology is associated with more aggressive metastasis and disease recurrence. We characterized nuclear morphology and function over time as prostate cancer cells underwent chemotherapeutic treatment and recovery to identify the unique characteristics that allow a cancer cell under stress to survive in the PACC state. We found that mononucleated cancer cells dominate the pool of cells in the PACC state that survive days after cisplatin treatment. Additionally, by examining markers of DNA damage and the DNA damage response, we found that cells that access the PACC state likely employ more successful DNA damage repair. Lastly, while many prostate cancer cells treated with a genotoxic agent succumb to apoptosis in the days following treatment release, our data suggest that surviving cancer cells must regulate a balance autophagy levels to restore cellular homeostasis while not initiating autophagic cell death. Together, our findings present a course of events that take place as a treated cancer cell recovers from chemotherapy and access the PACC state, representing an important set of findings to the understanding of therapy resistance and recurrence.