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Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma, comprised of extracellular matrix, cancer-associated fibroblasts (CAFs), and immune cells. Due to the rapid tumor growth and the unusually low blood vessel density of PDAC, both tumor cells and stromal cells experience hypoxia, or the low availability of oxygen. Although hypoxia is a crucial feature of the tumor milieu and predicts poor clinical outcome, the effects of hypoxia on the PDAC stromal cells, as well as the interplay between tumor and stroma, is not well understood. Cancer-associated fibroblasts (CAFs) are a predominant and heterogeneous stromal cell type in PDAC, and single-cell transcriptomics of human and mouse PDAC revealed a distinct CAF subpopulation, inflammatory CAFs (iCAFs). These inflammatory fibroblasts produce high levels of cytokines and chemokines in PDAC, potentially contributing to its immunosuppressive microenvironment and tumorigenesis. By injecting a hypoxia probe into PDAC mouse models, we previously showed that iCAFs predominantly reside in oxygen- starved regions of the tumor. Furthermore, we observed that the hypoxia-related gene signature is positively enriched in iCAFs in human PDAC tissues. By exposing three-dimensional (3D) cocultures of pancreatic tumor cells and fibroblasts to hypoxia, we found that hypoxia induces IL1ɑ from tumor cells, thereby promoting iCAF formation. Importantly, tumor cell IL1ɑ was further elevated in the presence of hypoxic fibroblasts, implicating hypoxia as a modulator of bidirectional tumor cell-CAF interactions. Efforts are ongoing to understand the mechanism by which hypoxia regulates CAF phenotype by modulating the bidirectional crosstalk between tumor cells and fibroblasts in PDAC. Together, our study identifies hypoxia as a crucial environmental factor in promoting the iCAF phenotype, thus highlighting an instructive role of hypoxia in shaping the stromal microenvironment. Citation Format: Tenzin Ngodup, Ashley Mello, Katelyn Donahue. Role of hypoxia in fibroblast reprogramming in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr A037.
Ngodup et al. (Sun,) studied this question.