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

Year: 2022

Type: article

Abstract: Acquired resistance to carboplatin is a major obstacle to the cure of ovarian cancer, but its molecular underpinnings are still poorly understood and often inconsistent between in vitro modeling studies. Using sequential treatment cycles, multiple clones derived from a single ovarian cancer cell reached similar levels of resistance. The resistant clones showed significant transcriptional heterogeneity, with shared repression of cell cycle processes and induction of IFNα response signaling, and subsequent pharmacological inhibition of the JAK/STAT pathway led to a general increase in carboplatin sensitivity. 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.

Source: npj Systems Biology and Applications

DOI: 10.1038/s41540-022-00230-z

Authors: Alexander T. Wenzel, Devora Champa, Hrishi Venkatesh, Si Sun, Cheng-Yu Tsai, Jill P. Mesirov, Jack D. Bui, Stephen B. Howell, Olivier Harismendy

Institutions: University of California San Diego, Moores Cancer Center, University of Minnesota, Wuhan Union Hospital, Huazhong University of Science and Technology, Stanford Medicine, Stanford University

Language: English

Topic: Ovarian cancer diagnosis and treatment

Subfield: Reproductive Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,090

Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Hartwell Foundation, National Institutes of Health, University of California, San Diego, National Cancer Institute, U.S. National Library of Medicine, Congressionally Directed Medical Research Programs

OpenAlex ID: W4283009136