Aerobic Exercise Activates S1PR1 Signaling in Tumor Endothelial Cells to Promote Vascular Function in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by high resistance to anti-cancer therapies, which is caused in part by hypo-vascularization and dysfunctional vessels that inefficiently deliver chemotherapy. Exercise has been shown to improve tumor vascular function and chemotherapy efficacy in preclinical models. Uncovering the mechanism by which exercise modifies tumor vasculature could help identify potential strategies to improve drug delivery. Here, we evaluated surgically resected PDAC from patients who exercised during neoadjuvant chemotherapy to demonstrate that exercise remodeled PDAC vasculature and improved tumor vascular function in patients. In mice bearing orthotopic PDAC and treadmill exercise, tumor vascular remodeling was dependent on sphingosine-1-phosphate receptor 1 (S1PR1) signaling in endothelial cells, and S1PR1 was necessary for improved chemotherapy efficacy by exercise. Exercise activated S1PR1 in tumor endothelium, improved tumor vascular function, and increased gemcitabine delivery and efficacy. Mice with an endothelial cell-specific S1PR1 deletion did not display exercise-induced improvements in tumor vascular function or gemcitabine efficacy. These findings demonstrate that exercise increases chemotherapy delivery and efficacy by improving vascular function, defining S1PR1 as a necessary mediator of exercise-induced vascular remodeling.