Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines

Abstract Cancer-associated fibroblasts (CAF) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAF) and inflammatory CAFs (iCAF) that are thought to have opposing roles in tumor progression. 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 displayed a hypoxic gene expression and biochemical profile and were enriched in hypoxic regions of PDAC tumors, while myCAFs were excluded from these regions. Hypoxia led fibroblasts to acquire an inflammatory gene expression signature and synergized with cancer cell–derived cytokines to promote an iCAF phenotype in a HIF1α-dependent fashion. Furthermore, HIF1α stabilization was sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid cocultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC. Significance: Hypoxia in the tumor microenvironment of pancreatic cancer potentiates the cytokine-induced inflammatory CAF phenotype and promotes tumor growth. See related commentary by Fuentes and Taniguchi, p. 1560