1. Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer
- Author
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Kaiyang Zhang, Erdogan 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, Research Program in Systems Oncology, Sampsa Hautaniemi / Principal Investigator, Genome-Scale Biology (GSB) Research Program, HUSLAB, HUS Children and Adolescents, Precision Cancer Pathology, Department of Pathology, Olli Mikael Carpen / Principal Investigator, Faculty Common Matters (Faculty of Medicine), and Bioinformatics
- Subjects
Ovarian Neoplasms ,EXPRESSION ,Multidisciplinary ,Drug Resistance, Neoplasm ,Sequence Analysis, RNA ,MUTATIONS ,Exome Sequencing ,3122 Cancers ,Humans ,Female ,HETEROGENEITY ,Transcriptome ,EVOLUTION - Abstract
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.
- Published
- 2022
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