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Updated: Sep 7, 2025
Enrichment for Chemoresistant Ovarian Cancer Stem Cells from Human Cell Lines
Published on: September 10, 2014
Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer
Alexander T Wenzel1,2, Devora Champa3,4, Hrishi Venkatesh5,6
1UC San Diego Bioinformatics and Systems Biology Graduate Program, San Diego, CA, USA.
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.
Insights
Acquired resistance to carboplatin chemotherapy shows significant cell-to-cell variability. Understanding proliferative and quiescent cell states is key to overcoming drug resistance and improving treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- The mechanisms of acquired resistance to carboplatin chemotherapy are not well understood.
- In vitro studies often yield inconsistent findings regarding carboplatin resistance.
- Understanding cellular heterogeneity is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the molecular basis of acquired resistance to carboplatin.
- To explore transcriptional heterogeneity in isogenic clones developing resistance.
- To evaluate the role of cell cycle phases (proliferative and quiescent) in carboplatin resistance.
Main Methods:
- Utilized gene-expression data from 26,772 single cells across four resistant clones and two treatment steps.
- Employed virtual synchronization to analyze Hallmark gene set activity in proliferative (P) and quiescent (Q) phases.
- Compared transcriptional profiles of resistant clones at different stages of treatment.
Main Results:
- Identified two key behaviors associated with carboplatin resistance: broad gene repression in the P phase and prevalent gene induction in the Q phase.
- Observed clone-specific induction of IFNα response in P phase or Wnt-signaling in Q phase.
- Highlighted significant transcriptional heterogeneity despite similar resistance levels across clones.
Conclusions:
- Proposed a model of 'resistance hysteresis' where alterations in P and Q phase states influence drug response dynamics.
- Emphasized the need for precise single-cell state monitoring to optimize chemotherapy schedules and combinations.
- Suggests that targeting specific cell states may overcome carboplatin resistance.
