Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer
Abstract
The molecular underpinnings of acquired resistance to carboplatin are poorly understood and often inconsistent between in vitro modeling studies. After sequential treatment cycles, multiple isogenic clones reached similar levels of resistance, but significant transcriptional heterogeneity. Gene-expression based virtual synchronization of 26,772 single cells from 2 treatment steps and 4 resistant clones was used to evaluate the activity of Hallmark gene sets in proliferative (P) and quiescent (Q) phases. Two behaviors were associated with resistance: (1) broad repression in the P phase observed in all clones in early resistant steps and (2) prevalent induction in Q phase observed in the late treatment step of one clone. Furthermore, the induction of IFNα response in P phase or Wnt-signaling in Q phase were observed in distinct resistant clones. These observations suggest a model of resistance hysteresis, where functional alterations of the P and Q phase states affect the dynamics of the successive transitions between drug exposure and recovery, and prompts for a precise monitoring of single-cell states to develop more effective schedules for, or combination of, chemotherapy treatments.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 17, 2022
- Source ID
- 10.1038/s41540-022-00230-z
Entities
People
- Alexander T. Wenzel
- Cheng‐Yu Tsai
- Devora Champa
- Hrishi Venkatesh
- Jack D. Bui
- Jill P. Mesirov
- Olivier Harismendy
- Si Sun
- Stephen B. Howell
Organizations
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- United States Department of Health and Human Services