2. Academic Validation
  3. Coordinated protein modules define DNA damage responses to carboplatin at single cell resolution in human ovarian carcinoma models

Coordinated protein modules define DNA damage responses to carboplatin at single cell resolution in human ovarian carcinoma models

  • bioRxiv. 2024 Nov 26:2024.11.21.624591. doi: 10.1101/2024.11.21.624591.
Jacob S Bedia 1,  Ying-Wen Huang 1,  Antonio Delgado Gonzalez 1,  Veronica D Gonzalez 2,  Ionut-Gabriel Funingana 3 4 5,  Zainab Rahil 2,  Alyssa Mike 1,  Alexis Lowber 1,  Maria Vias 4,  Alan Ashworth 6,  James D Brenton 4 5,  Wendy J Fantl 1 7 8
Affiliations

Affiliations

  • 1 Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Department of Oncology, University of Cambridge, Cambridgeshire, UK.
  • 4 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, Cambridgeshire, CB2 0RE, UK.
  • 5 Department of Oncology, Addenbrooke's Hospital, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK.
  • 6 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 Third Street, San Francisco, CA 94158, USA.
  • 7 Stanford Comprehensive Cancer Institute.
  • 8 Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
PMID: 39605494 DOI: 10.1101/2024.11.21.624591
Abstract

Tubo-ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy and frequently responds to platinum-based chemotherapy because of common genetic and somatic impairment of DNA damage repair (DDR) pathways. The mechanisms of clinical platinum resistance are diverse and poorly molecularly defined. Consequently, there are no biomarkers or medicines that improve patient outcomes. Herein we use single cell mass cytometry (CyTOF) to systematically evaluate the phosphorylation and abundance of proteins known to participate in the DNA damage response (DDR). Single cell analyses of highly characterized HGSC cell lines that phenocopy human patients show that cells with comparable levels of intranuclear platinum, a proxy for carboplatin uptake, undergo different cell fates. Unsupervised analyses revealed a continuum of DDR responses. Decompositional methods were used to identify eight distinct protein modules of carboplatin resistance and sensitivity at single cell resolution. CyTOF profiling of primary and secondary platinum-resistance patient models shows that a complex DDR sensitivity module is strongly associated with response, suggesting it as a potential tool to clinically characterize complex drug resistance phenotypes.

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