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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Tubo-ovarian high-grade serous carcinoma (HGSC) is a lethal gynecological cancer.
• Platinum-based chemotherapy is a common treatment, but resistance mechanisms are poorly understood.
• Lack of biomarkers hinders effective treatment strategies for HGSC.

Purpose of the Study:

• To systematically evaluate DNA damage response (DDR) protein phosphorylation and abundance in HGSC using single-cell mass cytometry.
• To identify molecular mechanisms underlying carboplatin resistance and sensitivity at a single-cell level.
• To explore potential biomarkers for predicting patient response to platinum chemotherapy.

Main Methods:

• Single-cell mass cytometry (CyTOF) was employed to analyze protein expression in HGSC cell lines and patient models.
• Cells were characterized based on intranuclear platinum levels as a proxy for carboplatin uptake.
• Unsupervised and decompositional analyses were used to identify distinct protein modules associated with drug response.

Main Results:

• HGSC cells with similar platinum levels displayed varied cell fates and DDR responses.
• A continuum of DDR responses was observed, revealing complexity in cellular reactions to carboplatin.
• Eight distinct protein modules related to carboplatin resistance and sensitivity were identified at single-cell resolution.
• A complex DDR sensitivity module was significantly associated with treatment response in patient-derived models.

Conclusions:

• Single-cell mass cytometry provides a powerful approach to dissecting complex drug resistance phenotypes in HGSC.
• The identified DDR sensitivity module shows potential as a clinical biomarker for characterizing platinum resistance.
• Further research into this module could lead to improved therapeutic strategies for HGSC patients.