期刊
SCIENCE ADVANCES
卷 8, 期 8, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abm1831
关键词
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资金
- European Union [667403, 965193]
- Academy of Finland [344697, 325956, 289059, 322927, 294023, 319243]
- Sigrid Juselius Foundation
- Cancer Foundation Finland
- Academy of Finland (AKA) [325956, 322927, 294023, 289059, 344697, 319243, 322927, 325956, 319243, 289059, 294023] Funding Source: Academy of Finland (AKA)
Chemotherapy resistance is a major contributor to cancer mortality, and a study focusing on high-grade serous ovarian cancer found that a stress-associated cell state consistently increased during chemotherapy, which was associated with poor progression-free survival.
Chemotherapy resistance is a critical contributor to cancer mortality and thus an urgent unmet challenge in oncology. To characterize chemotherapy resistance processes in high-grade serous ovarian cancer, we prospectively collected tissue samples before and after chemotherapy and analyzed their transcriptomic profiles at a single-cell resolution. After removing patient-specific signals by a novel analysis approach, PRIMUS, we found a consistent increase in stress-associated cell state during chemotherapy, which was validated by RNA in situ hybridization and bulk RNA sequencing. The stress-associated state exists before chemotherapy, is subclonally enriched during the treatment, and associates with poor progression-free survival. Co-occurrence with an inflammatory cancer-associated fibroblast subtype in tumors implies that chemotherapy is associated with stress response in both cancer cells and stroma, driving a paracrine feed-forward loop. In summary, we have found a resistant state that integrates stromal signaling and subclonal evolution and offers targets to overcome chemotherapy resistance.
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