Abstract 1586: Unraveling the importance of pancreatic cancer extracellular signaling to endothelial cells within the tumor microenvironment

Abstract

Abstract In many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), the secretion of extracellular vesicles (EVs) has been shown to support tumor progression, chemotherapeutic resistance, and metastasis. Importantly, PDAC tumors are composed of up to 80% non-tumor cells and an extracellular matrix, yet no studies have been performed to determine which cells within PDAC tumors internalized PDAC EVs. Further, the RNA-binding protein HuR plays an important role in PDAC cells, supporting the stability and translation of transcripts that aid tumor cell stress responses. Our lab has recently found that EVs harbor distinct mRNA and phosphorylated protein cargoes from donor cells. Further, HuR knockout (KO) cells produce EVs with significantly different mRNAs and phosphorylated proteins that EVs isolated from HuR wildtype (WT) cells. Specifically, proteins relating to endothelial function and angiogenesis were significantly differentially phosphorylated. Considering the functional impact of EV cargoes on recipient cells, our study aims to identify the specific cell types in the tumor microenvironment that import PDAC EVs and investigate the role of PDAC cell HuR in this signaling process. We have generated human PDAC and mouse KrasG12D Trp53R172H driven (KPC) PDAC cell lines to express an EV reporter, PalmGRET. Utilizing these cells lines in an immunocompetent mouse model of PDAC, we found that endothelial cells are major importers of PDAC EVs. We next performed bulk RNA-sequencing on endothelial cells sorted from these tumors that have (GFP+) versus have not (GFP-) imported PDAC EVs to assess the functional impact of PDAC EVs. Subsequent studies will focus on delineating the importance of this signaling axis by ablating EV secretion in addition to assessing endothelial cell function when treated with EVs from HuR WT vs. KO cells. Collectively, our study sheds light on the preferential uptake of PDAC EVs by endothelial cells and highlights the potential role of tumor cell-intrinsic HuR in this signaling process. These findings expand our understanding of the interactions between PDAC and the tumor microenvironment, potentially paving the way for targeted therapeutic interventions in this devastating disease. Citation Format: Jennifer M. Finan, Yifei Guo, Alexandra Q. Bartlett, Kevin MacPherson, Valerie Calvert, Madeline D. Hedberg, Emanuel Petricoin, Rosalie Sears, Jonathan R. Brody. Unraveling the importance of pancreatic cancer extracellular signaling to endothelial cells within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1586.