Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer
Häkkinen Antti; Hautaniemi Sampsa; Andersson Noora; Oikkonen Jaana; Carpén Olli; Hynninen Johanna; Jamalzadeh Sanaz; Mansuri Naziha; Virtanen Anni; Huhtinen Kaisa; Lamminen Tarja; Vähärautio Anna; Kaipio Katja; Hietanen Sakari; Dai Jun; Erkan Erdogan Pekcan; Zhang Kaiyang
Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer
Häkkinen Antti
Hautaniemi Sampsa
Andersson Noora
Oikkonen Jaana
Carpén Olli
Hynninen Johanna
Jamalzadeh Sanaz
Mansuri Naziha
Virtanen Anni
Huhtinen Kaisa
Lamminen Tarja
Vähärautio Anna
Kaipio Katja
Hietanen Sakari
Dai Jun
Erkan Erdogan Pekcan
Zhang Kaiyang
AMER ASSOC ADVANCEMENT SCIENCE
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022081154932
https://urn.fi/URN:NBN:fi-fe2022081154932
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]