Exercise modulates microbial metabolites and induces stromal remodeling in pancreatic cancer.

Abstract

Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, a better understanding of the clinical effects of exercise and mediating mechanisms is needed to maximize the utility of exercise for patients. In this study, we analyzed tumors from pancreatic ductal adenocarcinoma (PDAC) patients in the PancFit trial and identified an exercise induced reduction in cells expressing alpha smooth muscle actin (αSMA). Interrogation of changes in tumor stromal composition with exercise in a murine PDAC model revealed a microbially-influenced reduction in αSMA+ cells and IL6 expressing inflammatory cancer associated fibroblasts (iCAFs). Cholic acid, a microbial bile acid, was increased in both patients and murine models with exercise, as a potential mediator of exercise induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 expression, supporting a stromal remodeling effect of physical activity. In summary, this study demonstrates that the anti-tumor effect of exercise includes stromal remodeling which is impacted by microbial metabolites.