Abstract 3850: Aberrant tumor pericytes in pancreatic ductal adenocarcinoma-a barrier and opportunity for therapeutic advances

Abstract There is a lack of effective treatment for PDAC, often due to abnormal and leaky blood vessels and a lack of proper pericyte coverage, contributing to the inability of the drugs to reach the tumor. We and others showed that pericyte (PC) coverage significantly correlates with vascular integrity, function, and intratumoral hypoxia. However, in PDAC, the PC-endothelial (EC) cell communication is decreased or non-existent, thereby affecting drug delivery and immune function. We propose to re-program tumor-associated pericytes to normalize the tumor blood vessels and revert them to an optimal functional state. We previously showed that tumor-associated pericytes in PDAC exhibit ectopic αSMA expression up to ten times higher than normal pericytes, correlating strongly with vascular instability and hypoxia. Due to significant involvement of αSMA in cellular morphology and structure, tumor-associated pericytes presented biomechanical abnormalities, which diminished intimate association with endothelial cells during tube formation assay. We employed scRNA sequencing to define the pathological signature of tumor-associated pericytes and identify therapeutic targets for vascular normalization. Our analysis revealed considerable heterogeneity in lung pericytes compared to PDAC pericyte clusters, indicating a disrupted vessel hierarchy. Additionally, we identified a distinct pericyte subpopulation characterized by elevated expression of αSMA, MCT1, and gap junction proteins. Alterations in basement membrane gene expression and smooth muscle markers further emphasized the disrupted vascular architecture and impaired pericyte-endothelial cell adhesion within the tumor microenvironment. Our data reveals consistently upregulated monocarboxylate transporters in vascular cells. Therefore, we investigated lactate transporters as a potential target for improving PC-EC adhesion. We have shown that in PDAC, MCT1 lactate exporters are upregulated in EC and PCs. The high amount of lactate produced by PCs decreases the pH in the basement membrane. So, we knocked down MCT1 transporters in PCs to increase basement pH, leading to improved PC-EC attachment and pericyte homeostasis. 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 tumor pericytes in pancreatic ductal adenocarcinoma-a barrier and opportunity for therapeutic advances [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3850.