Open AccessLongitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer
Author(s) -
Kaiyang Zhang,
Erdoğan Pekcan Erkan,
Sanaz Jamalzadeh,
Jun Dai,
Noora Andersson,
Katja Kaipio,
Tarja Lamminen,
Naziha Mansuri,
Kaisa Huhtinen,
Olli Carpén,
Sakari Hietanen,
Jaana Oikkonen,
Johanna Hynninen,
Anni Virtanen,
Antti Häkkinen,
Sampsa Hautaniemi,
Anna Vähärautio
Publication year - 2022
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abm1831
Subject(s) - chemotherapy , ovarian cancer , stromal cell , transcriptome , cancer research , paracrine signalling , single cell analysis , biology , serous fluid , oncology , cancer , medicine , cell , gene , gene expression , genetics , receptor
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.