Cancer-Associated Fibroblasts Promote Epithelial–Mesenchymal Transition and Classical to Basal Subtype Shift in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer-associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy, and multiple CAF subtypes have been defined. However, defining the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior is required to better characterize the role of CAFs in PDAC. In this study, we used multiomic analyses to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs promoted epithelial-mesenchymal transition and a switch in tumor cell classification from classical to basal subtype. Furthermore, CAF-specific interleukin 8 functioned as a modulator of tumor cell subtype. Finally, neighborhood relationships between tumor cells and T cell subsets were defined, demonstrating a distinct spatial coordination among CAF and tumor cell subtypes. Overall, this study provides data supporting CAF signaling as a regulator of the cellular and behavioral heterogeneity in the PDAC TME. These findings can be used to explore rational approaches to improve therapies for this difficult-to-treat disease. SIGNIFICANCE: Multidimensional analyses highlight the diverse role of cancer-associated fibroblasts in influencing cells in the tumor microenvironment and provide a platform for evaluating emerging therapeutic approaches and studying mechanisms dictating tumor behavior.