Characterizing pancreatic cancer-associated fibroblast heterogeneity in vascular microphysiological systems

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), one of the deadliest cancer types, is dominated by a tumor microenvironment (TME) that is desmoplastic, immunosuppressive, and generally unresponsive to conventional cancer treatments. Cancer-Associated Fibroblasts (CAFs) are thought to drive many of the features of PDAC that contribute to treatment resistance, yet CAFs exhibit wide phenotypic heterogeneity with unclear biological and clinical implications. Recent work has identified CAF subtypes – tumor-restraining CAFs (RestCAFs) or tumor-promoting CAFs (ProCAFs) – that correlate with overall survival. Therefore, this study aims to identify CAF subtype-dependent functional effects in the TME using 3D microphysiological systems, focusing primarily on their interactions with vasculature. Microfluidic devices including a RestCAF line demonstrated increased levels of vasculogenesis and extracellular matrix remodeling, while devices containing a ProCAF line exhibited increased angiogenic sprouting and differential immune cell recruitment, such as monocyte migration into the TME. This work provides novel insights into the heterogeneous functions of CAFs in the TME and lays important groundwork for the development of CAF-targeted therapies in PDAC.