Abstract B039: Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is notable for its dense desmoplastic stroma, consisting of extracellular matrix, cancer-associated fibroblasts (CAFs), and immune cells. Another notable feature of the PDAC microenvironment is hypoxia, a condition of insufficient oxygen availability. Although hypoxia leads to adaptive responses in both cancer cells and stromal cells, the effects of hypoxia on the PDAC stroma and tumor-stroma interactions are not fully understood. Cancer-associated fibroblasts (CAFs) are a predominant and heterogeneous stromal cell type in PDAC, and single-cell transcriptomics of human and mouse PDAC has recently revealed a distinct CAF subpopulation, inflammatory CAFs (iCAFs). These inflammatory fibroblasts produce high levels of cytokines and chemokines in PDAC and have the potential to contribute to its immunosuppressive microenvironment and tumorigenesis. By injecting a hypoxia probe into PDAC mouse models, we recently found that iCAFs predominantly reside in hypoxic tumor regions. We also observed that the hypoxia-related gene signature is positively enriched in iCAFs in human PDAC samples. By exposing 3D cocultures of pancreatic tumor cells and fibroblasts to either hypoxia or normoxia, we demonstrated that hypoxia promotes iCAF formation via IL1ɑ secreted from tumor cells. Importantly, the presence of hypoxic fibroblasts further elevated IL1ɑ levels in tumor cells, implicating hypoxia as a modulator of bidirectional interactions between tumor cells and fibroblasts. Efforts are ongoing to understand the mechanism by which hypoxia promotes iCAF formation by modulating bidirectional interactions between tumor cells and fibroblasts in PDAC. Together, our study identifies hypoxia as a key environmental cue for inducing an iCAF phenotype, thus highlighting an instructive role of hypoxia in shaping the stromal microenvironment. Citation Format: Tenzin Ngodup, Ashley Mello. Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B039.