Abstract B074: Aberrant pericytes in PDAC: effects on endothelial-pericyte adhesion, vascular integrity, and tumor microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in men and women in the U.S., with a 5-year survival rate of 13%. Within the PDAC tumor microenvironment (TME), morphologically aberrant leaky vessels are responsible for hypoxia and impaired immune response, which likely reduces the efficacy of cancer therapies. We and others showed that pericyte (PC) coverage significantly correlates with vascular integrity, function, and intratumor hypoxia. Therefore, understanding the contribution of abnormal PC to the TME evolution is a critical step toward PDAC treatment options. Consequently, we hypothesize that correcting such undesirable phenotype via vascular normalization will enhance treatment efficacy. Our study revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic alpha-smooth muscle actin (αSMA) cytoskeletal protein expression up to 10 times higher than normal pericytes, which was significantly correlated with vascular leakiness and hypoxia. Our previous publication showed that PDAC-derived extracellular vesicles are potent inducers of αSMA expression in pericytes characterized by biomechanical abnormalities. To evaluate the vascular functional defect, we performed a tube formation assay showing abnormal pericytes contribute to abnormal vasculatures in vitro. Our investigation aims to uncover the cause of the abnormal pericyte phenotype that disrupts the physical adhesion between pericytes and endothelial cells (EC), resulting in compromised vasculature. Our findings reveal consistently upregulated monocarboxylate transporters in vascular cells. To enhance EC-pericyte adhesion, we investigated lactate metabolic communication, which is tightly linked due to the proximity of ECs and pericytes. We have shown that in PDAC, MCT1 lactate exporters are upregulated in EC. Conversely, MCT12 lactate importers are highly expressed in pericytes. The high amount of lactate produced by ECs decreases the pH in the basement membrane. So, we knocked down MCT1 transporters in ECs to increase basement pH, leading to improved PC-EC attachment and pericyte homeostasis. Finally, we performed single-cell RNA sequencing to determine the pathological signature of tumor pericytes and identify potential target molecules for vascular normalization. In conclusion, our study indicates that tumor-associated pericytes undergo phenotype switching and disturbed metabolic communication under the influence of pancreatic cancer cells. These aberrant pericytes might contribute to non-optimal vascular integrity and function. Single-cell RNA sequencing helped understand the molecular signature of the PDAC pericyte, providing a powerful tool to develop novel targeting strategies for vascular normalization. Future work includes exploring the vascular normalization approach by suppressing pericyte phenotype switching to enhance vascular function and chemo- and immunotherapeutic efficacy. Citation Format: Vikneshwari Natarajan, Sangdeuk Ha, Jiha Kim. Aberrant pericytes in PDAC: effects on endothelial-pericyte adhesion, vascular integrity, and tumor microenvironment [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 Suppl_2):Abstract nr B074.