Oncotarget

Research Papers:

Avoidance of apoptotic death via a hyperploid salvage survival pathway after platinum treatment in high grade serous carcinoma cell line models

Tony Yeung, Oliver Fung, Mikhail Bashkurov, Arian Khandani, Omar Subedar, Alexandra Wudwud, Patricia Shaw, Blaise Clarke, John Bartlett, Robert Rottapel _ and Andras Kapus _

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Oncotarget. 2019; 10:6691-6712. https://doi.org/10.18632/oncotarget.27330

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Abstract

Tony Yeung1, Oliver Fung1, Mikhail Bashkurov2, Arian Khandani3, Omar Subedar3, Alexandra Wudwud4, Patricia Shaw4, Blaise Clarke4, John Bartlett5, Robert Rottapel4,5,6,7,8,9 and Andras Kapus1

1 St. Michael’s Hospital, Keenan Research Center, Toronto, Canada

2 Network Biology Collaborative Centre, Toronto, Canada

3 Flow and Mass Cytometry Facility, Hospital for Sick Children, Toronto, Canada

4 Princess Margaret Cancer Center at the University Health Network, Toronto, Canada

5 Ontario Institute for Cancer Research, University of Toronto, Toronto, Canada

6 Department of Medicine, University of Toronto, Toronto, Canada

7 Division of Rheumatology, St. Michael’s Hospital, Toronto, Canada

8 Department of Immunology, University of Toronto, Toronto, Canada

9 Department of Medical Biophysics, University of Toronto, Toronto, Canada

Correspondence to:

Robert Rottapel,email: rottapel@uhnresearch.ca
Andras Kapus,email: andras.kapus@unityhealth.to

Keywords: hyperploid genome; apoptosis; platinum chemotherapy; cell cycle checkpoint; ovarian cancer

Received: May 27, 2019     Accepted: October 26, 2019     Published: November 19, 2019

ABSTRACT

The alkylating agent platinum is first-line chemotherapy treatment for high-grade serous carcinomas (HGSC) of tubal-ovarian origin. Platinum compounds cause DNA damage and induce apoptotic cell death in the bulk tumor population. However, subpopulations of tumor cells may exhibit diverging behaviors from the bulk tumor due to an alternate stress response that diverts tumor cells from apoptotic death. In this study, we identified a salvage survival pathway in which G2-arrested tumor cells bypassed apoptosis and progressed through aberrant mitotic events to then emerge as a distinct subpopulation of viable large hyperploid cells but with uncertain long-term propagation potential. Platinum-induced large hyperploid cells were flow sorted and showed rare regrowth capacity as compared to their more proficiently regenerating non-hyperploid counterparts. However, detailed time-lapse microscopy provided direct evidence that these hyperploid cells were mitotically active and could divide successfully to produce viable daughter cells. The hyperploid survival response was observed across different cell lines and utilization of this survival pathway was dependent on the strength of the G2-M checkpoint. Conceivably, this salvage survival strategy may contribute to increased genomic diversity of the regenerating tumor cell line through a coupled hyperploidization and de-polyploidization process that may be relevant for drug resistance.


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