Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer

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-expr...

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Bibliographic Details
Published in:NPJ systems biology and applications 2022-06, Vol.8 (1), p.20-9, Article 20
Main Authors: Wenzel, Alexander T., Champa, Devora, Venkatesh, Hrishi, Sun, Si, Tsai, Cheng-Yu, Mesirov, Jill P., Bui, Jack D., Howell, Stephen B., Harismendy, Olivier
Format: Article
Language:English
Subjects:
631/553/1833
692/4028/67
Bioinformatics
Biomedical and Life Sciences
Carboplatin
Carboplatin - pharmacology
Carboplatin - therapeutic use
Chemotherapy
Cloning
Computational Biology/Bioinformatics
Computer Appl. in Life Sciences
Female
Gene expression
Humans
Life Sciences
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Synchronization
Systems Biology
Wnt protein
α-Interferon
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Summary: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.
ISSN:2056-7189
2056-7189
DOI:10.1038/s41540-022-00230-z