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

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 myofi- broblastic 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 syner-gized with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF1a-dependent fashion. Furthermore, HIF1a 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 HIF1a as a regulator of CAF heterogeneity and pro-moter of tumor progression in PDAC.

Automated summary

Cancer-associated fibroblasts (CAF) in pancreatic ductal adenocarcinoma (PDAC) exhibit heterogeneity, with myofi-broblastic CAFs (myCAF) and inflammatory CAFs (iCAF) having opposing roles. In vivo, iCAFs show a hypoxic gene expression profile and are enriched in hypoxic regions of PDAC tumors, while myCAFs are excluded from these areas. Hypoxia induces an inflammatory gene expression signature in fibroblasts and synergizes with cancer cell-derived cytokines to promote the iCAF phenotype. HIF1a stabilization is sufficient to induce the iCAF phenotype and promote PDAC tumor growth.