Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. This functional heterogeneity is correlated with the existence of transcriptionally distinct subpopulations of CAFs. CAF heterogeneity is observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a remarkably dense and hypoxic stroma that features tumor-restraining myofibroblastic CAFs (myCAFs) and tumor-supporting inflammatory CAFs (iCAFs). While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs display a hypoxic gene expression and biochemical profile and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads fibroblasts to acquire an inflammatory gene expression signature and synergizes with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1 dependent fashion. Furthermore, we show that HIF-1 stabilization is sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1 as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.