HuR-Regulated Extracellular Vesicles Promote Endothelial Cell Remodeling in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors are hypovascular with collapsed and dysfunctional vessels that limit immunosurveillance and contribute to early metastatic events. However, current antiangiogenic therapies have failed in PDAC, highlighting the need to uncover the mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein human antigen R (HuR; ELAVL1) plays an important role in reshaping the tumor microenvironment by regulating the stability and translation of cell communication-encoding transcripts. We demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the tumor microenvironment via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. PDAC EVs contain an HuR-dependent mRNA and protein cargo related to endothelial cell function and angiogenesis. Treating endothelial cells with HuR wild-type (WT) EVs increased the expression of genes involved in barrier function and endothelial cell development and increased their migratory and tube-forming functions. In an immunocompetent mouse model of PDAC, we showed that HuR increased endothelial cell presence and sprouting, while decreasing intercellular adhesion molecule 1 (ICAM-1) expression. Using a genetic EV reporter, we found that ICAM-1 suppression in WT tumors occurred specifically in endothelial cells that had internalized WT EVs, suggesting that this signaling axis modulates endothelial cell behavior in vivo. Furthermore, administration of WT EVs rescued impaired HuR-knockout tumor growth, increased endothelial cell abundance, and decreased endothelial cell ICAM-1 expression. Collectively, our data reveal a novel role for HuR as a key mediator of EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior. SIGNIFICANCE: Targeting the abnormal pancreatic cancer vasculature remains a significant barrier to immunosurveillance and drug delivery. This study demonstrated that the tumor-intrinsic protein HuR regulates pancreatic cancer EVs, which, in turn, alters endothelial cell behavior. These findings reveal a novel mechanism by which tumor-intrinsic factors shape the vascular microenvironment and suggest that altering EV content could modulate endothelial cell function.