ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

Area of Science:

• Oncology
• Cell Biology
• Genomics

Background:

• High-grade serous ovarian cancer (HGSOC) is the deadliest subtype.
• Relapse is common despite initial platinum-based therapy, often due to drug-tolerant persister (DTP) cells.

Purpose of the Study:

• Investigate the characteristics of DTP cells in HGSOC.
• Identify molecular mechanisms driving HGSOC relapse.
• Explore therapeutic targets to overcome treatment resistance.

Main Methods:

• Generated isogenic HGSOC clones (treatment-naïve and cisplatin-tolerant).
• Performed single-cell RNA sequencing in xenograft models and patient samples.
• Analyzed TCGA data for survival correlations.

Main Results:

• DTP-derived cells showed altered morphology and increased epithelial-mesenchymal transition (EMT) markers.
• Aggressive DTP cells overexpressed the stress marker ATF3; ATF3 knockdown increased cisplatin sensitivity.
• Relapsed tumors and patient samples revealed increased EMT and ER stress markers, including ATF3.
• Low expression of ATF3-associated partial EMT genes correlated with improved progression-free survival.

Conclusions:

• Increased ATF3 expression and partial EMT contribute to aggressive DTP formation and HGSOC relapse.
• ATF3 and EMT pathways are potential therapeutic targets for overcoming cisplatin resistance in HGSOC.