| RRC ID |
85941
|
| Author |
Bedia JS, Delgado-Gonzalez A, Huang YW, Gonzalez VD, Funingana IG, Rahil Z, Mike A, Lowber A, Vias M, Ashworth A, Brenton JD, Fantl WJ.
|
| Title |
Coordinated protein modules define DNA damage responses to carboplatin at single-cell resolution in human ovarian carcinoma models.
|
| Journal |
Cell Rep Med
|
| Abstract |
Tubo-ovarian high-grade serous carcinoma (HGSC), the most lethal gynecologic malignancy, initially responds to platinum-based chemotherapy, but due to frequent defects in the DNA damage response (DDR), most tumors develop resistance. The molecular mechanisms underlying clinical platinum resistance remain poorly defined with no biomarkers or targeted therapies to improve outcomes. Here, applying mass cytometry, we quantify phosphorylation and abundance of DDR proteins in carboplatin-treated HGSC cell line models. Despite similar levels of intranuclear platinum, a proxy for carboplatin uptake, cells follow divergent fates, reflecting DDR heterogeneity. Unsupervised analysis reveals a continuum of DDR states, and matrix factorization identifies eight protein modules. The activity of one module, containing canonical DDR proteins, increases in carboplatin-sensitive cells. Resistant cells engage a broader DDR protein module. These findings demonstrate the ability of single-cell proteomics to identify functional DDR states and reveal a DDR sensitivity module as a promising biomarker for clinical stratification and therapeutic decisions in HGSC.
|
| Volume |
6(9)
|
| Pages |
102295
|
| Published |
2025-9-16
|
| DOI |
10.1016/j.xcrm.2025.102295
|
| PII |
S2666-3791(25)00368-4
|
| PMID |
40848720
|
| MeSH |
Antineoplastic Agents / pharmacology
Carboplatin* / pharmacology
Carboplatin* / therapeutic use
Cell Line, Tumor
DNA Damage* / drug effects
DNA Repair / drug effects
Drug Resistance, Neoplasm / drug effects
Female
Humans
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / metabolism
Ovarian Neoplasms* / pathology
Phosphorylation / drug effects
Proteomics / methods
Single-Cell Analysis* / methods
|
| Resource |
| Human and Animal Cells |
JHOS-2(RCB1521) |
