Acquired αSMA Expression in Pericytes Coincides with Aberrant Vascular Structure and Function in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: The pancreatic cancer field suffers from a lack of effective treatment options in part due to the severely compromised tumor vasculature that leads to hypoxia and an immunosuppressive environment. Our study aimed to identify and characterize pathological pericyte phenotypes that contribute to the defective tumor vasculature. We found that a large population of PDAC pericytes present ectopic α-smooth muscle actin (αSMA) expression, and this subtype was induced by cancer cell-derived exosomes. We also showed that the PDAC exosome-induced αSMA(+) pericyte exhibits aberrant biomechanical properties and an acquired immunomodulatory phenotype. Considering a lack of efficient anti-angiogenic approaches in PDAC, identifying a unique molecular phenotype or the target molecule of a pathological pericyte will be an entry point toward a vascular normalization approach. ABSTRACT: The subpopulations of tumor pericytes undergo pathological phenotype switching, affecting their normal function in upholding structural stability and cross-communication with other cells. In the case of pancreatic ductal adenocarcinoma (PDAC), a significant portion of blood vessels are covered by an α-smooth muscle actin (αSMA)-expressing pericyte, which is normally absent from capillary pericytes. The Desmin(low)αSMA(high) phenotype was significantly correlated with intratumoral hypoxia and vascular leakiness. Using an in vitro co-culture system, we demonstrated that cancer cell-derived exosomes could induce ectopic αSMA expression in pericytes. Exosome-treated αSMA(+) pericytes presented altered pericyte markers and an acquired immune-modulatory feature. αSMA(+) pericytes were also linked to morphological and biomechanical changes in the pericyte. The PDAC exosome was sufficient to induce αSMA expression by normal pericytes of the healthy pancreas in vivo, and the vessels with αSMA(+) pericytes were leaky. This study demonstrated that tumor pericyte heterogeneity could be dictated by cancer cells, and a subpopulation of these pericytes confers a pathological feature.