Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer

: Zhang Kaiyang, Erkan Erdogan Pekcan, Jamalzadeh Sanaz, Dai Jun, Andersson Noora, Kaipio Katja, Lamminen Tarja, Mansuri Naziha, Huhtinen Kaisa, Carpén Olli, Hietanen Sakari, Oikkonen Jaana, Hynninen Johanna, Virtanen Anni, Häkkinen Antti, Hautaniemi Sampsa, Vähärautio Anna

Publisher: AMER ASSOC ADVANCEMENT SCIENCE

: 2022

: Science Advances

: SCIENCE ADVANCES

: SCI ADV

: eabm1831

: 8

: 18

: 2375-2548

DOI: https://doi.org/10.1126/sciadv.abm1831

: https://www.science.org/doi/10.1126/sciadv.abm1831

: https://research.utu.fi/converis/portal/detail/Publication/175009671

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.

sciadv.abm1831.pdf