Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC. [Display omitted] •HIF-1α-positive cancer cells and CAFs form chemoresistant niches of OCCC•PDGF from HIF-1α-positive cancer cells activates CAFs•Activated CAFs induce HIF-1α expression and chemoresistance in cancer cells•Inhibition of PDGF signaling in CAFs augments chemosensitivity of cancer cells Through an integration of spatial analyses and co-culture studies, Mori et al. demonstrate that feedback activation between HIF-1α-positive cancer cells and cancer-associated fibroblasts (CAF) contributes to chemoresistance of ovarian clear cell carcinoma. Targeted inhibition of CAF activation by a receptor tyrosine kinase inhibitor augmented chemosensitivity, suggesting possible application for CAF-targeted therapy.