Aberrant pericytes in pancreatic ductal adenocarcinoma: effects on endothelial-pericyte adhesion, vascular integrity, and tumor microenvironment

PDAC tumor microenvironment (TME) exhibits morphologically aberrant, leaky vessels, leading to hypoxia, impaired immune response, and reduced efficacy of cancer therapies. Evidently, pericyte (PC) coverage correlates with vascular integrity, function, and intratumoral hypoxia. We revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic αSMA expression up to 10 times higher than normal pericytes. These aberrant pericytes are characterized by biomechanical abnormalities correlated with vascular leakiness and hypoxia. We aim to uncover the cause of the abnormal PC phenotype that disrupts the physical adhesion between PCs and endothelial cells (EC). Our findings reveal the upregulation of monocarboxylate transporters in vascular cells. To enhance PC-EC adhesion, we investigated lactate metabolic communication, which is tightly linked due to the proximity, and showed that in PDAC, MCT1 lactate transporters are upregulated in PCs. The high amount of lactate produced by ECs decreases the pH in the basement membrane. So, increasing basement pH will improve PC-EC attachment and pericyte homeostasis. Finally, scRNA-seq helped to understand the molecular signature of the PDAC pericyte and identify potential target molecules for vascular normalization.