Abstract LB053: PDAC derived exosomes manipulate tumor pericyte phenotype

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 10%. This poor prognosis is partly due to the aggressive nature of the disease, lack of early detection methods, its complex and dense tumor microenvironment (TME), and lack of effective treatment options. Within the PDAC 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 coverage significantly correlates with vascular integrity/function and intratumoral hypoxia. Therefore, understanding perivascular heterogeneity and the unique contribution of each phenotype to the TME evolution is a critical step towards personalized treatment options for PDAC. Our study revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic αSMA expression up to 10X higher compared to the normal pericytes. This aberrant pericyte phenotype was correlated with vascular leakiness and hypoxia, whereas the Des+ mature pericyte phenotype was inversely correlated with vessel leakiness. Our attempt to elucidate the underlying mechanism of pericyte phenotype switching using in vitro culture system shows that pancreatic cancer cell-derived extracellular vesicles (PC-Exo) is a potent inducer of αSMA expression in pericyte. PC-Exo was also sufficient enough to induce αSMA expression in normal pericytes within the pancreas when injected into the WT mice. In addition to the changes in pericyte markers, PC-Exo stimulated pericytes exhibited immunomodulatory phenotype with significantly higher expression of HLA-DRA, CD274, CD80, E-selectin, and P-selectin. Considering αSMA is a cytoskeletal protein that can influence cellular stiffness, migration, and downstream signaling, we also examined the biomechanical properties of pericytes with altered phenotype. The results show a significant increase in pericyte stiffness and cellular height of aSMA+ pericyte. These pericytes also have elongated morphology and cytoskeletal reorganization visualized by αSMA and phalloidin immunostaining. A recent study showed that acquired αSMA expression converts capillary pericytes into contractile vascular smooth muscle-like cells. Blood vessels are constricted and collapsed within the PDAC TME, which may be partly caused by an abundance of αSMA+ pericytes. In conclusion, our study indicates that tumor-associated pericytes undergo phenotype switching under the influence of pancreatic cancer cells, and these aberrant pericytes might contribute to non-optimal vascular integrity/function. Together, our study indicates that tumor conditioned αSMA+ pericytes present mechanical abnormalities and immune-suppressive features. 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, Alexander Delgado, Reed Jacobson, Lina Alhalhooly, Yongki Choi, Sangdeuk Ha, Jiha Kim. PDAC derived exosomes manipulate tumor pericyte phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB053.