Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

Tiffany Lam, Julio A. Aguirre-Ghiso, Melissa A. Geller, Alptekin Aksan, Samira M. Azarin

Research output: Contribution to journalArticlepeer-review

Abstract

Around 20–30% of ovarian cancer patients exhibit chemoresistance, but there are currently no methods to predict whether a patient will respond to chemotherapy. Here, we discovered that chemoresistant ovarian cancer cells exhibit enhanced survival in a quiescent state upon experiencing the stress of physical confinement. When immobilized in stiff silica gels, most ovarian cancer cells die within days, but surviving cells exhibit hallmarks of single-cell dormancy. Upon extraction from gels, the cells resume proliferation but demonstrate enhanced viability upon reimmobilization, indicating that initial immobilization selects for cells with a higher propensity to enter dormancy. RNA-seq analysis of the extracted cells shows they have signaling responses similar to cells surviving cisplatin treatment, and in comparison to chemoresistant patient cohorts, they share differentially expressed genes that are associated with platinum-resistance pathways. Furthermore, these extracted cells demonstrate greater resistance to cisplatin and paclitaxel, despite being proliferative. In contrast, serum starvation and hypoxia could not effectively select for chemoresistant cells upon removal of the environmental stress. These findings demonstrate that ovarian cancer chemoresistance and the ability to enter dormancy are linked, and immobilization rapidly distinguishes chemoresistant cells. This platform could be suitable for mechanistic studies, drug development, or as a clinical diagnostic tool.

Original languageEnglish (US)
Pages (from-to)3066-3080
Number of pages15
JournalBiotechnology and bioengineering
Volume117
Issue number10
DOIs
StateAccepted/In press - 2020

Bibliographical note

Funding Information:
The authors would like to acknowledge the University of Minnesota Genomics Center and the Minnesota Supercomputing Institute for carrying out work and providing resources that contributed to the research results reported within this study. The authors would also like to thank Hak Rae Lee for assistance with western blot analysis experiments and Jennifer One for assistance with RNA-sequencing analysis. This study was supported by grant #IRG-16-189-58 from the American Cancer Society and Biotechnology Training Grant: NIHT32GM008347 (T. L.).

Keywords

  • chemoresistance
  • immobilization
  • ovarian cancer
  • quiescence
  • silica gel

PubMed: MeSH publication types

  • Journal Article

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