Host-intrinsic factors determine anti-tumor efficacy of exercise in pancreatic ductal adenocarcinoma
Author ORCID Identifier
0000-0001-6492-3849
Date of Graduation
12-2025
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Keri Schadler
Committee Member
Florencia McAllister
Committee Member
Seyed Javad Moghaddam
Committee Member
Matthew M. Gubin
Committee Member
Nancy Gordon
Committee Member
Emily LaVoy
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a low 5-year relative survival rate of approximately 13.3% for all stages combined. We have previously shown that exercise can improve quality of life and enhance functional capacity among patients with PDAC. Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, our understanding of the clinical effects of exercise and the mechanisms that mediate anti-tumor effects are limited in pancreatic cancer.
In this project, using C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), we established a pre-clinical mouse model of orthotopic PDAC with multiple exercise interventions. We demonstrated that gut microbiome differences between Tac and Jax result in differential exercise capacity with an intensity- dependent effect of exercise on tumor infiltrating immune cells.
We interrogated tumor stromal composition changes with exercise and observed a gut microbiome dependent reduction in alpha smooth muscle actin (αSMA+) cells and Il6 expressing inflammatory cancer associated fibroblasts (iCAFs). Similar analysis of tumors from patients in the PancFit trial demonstrated an exercise induced reduction in αSMA+ cells. We subsequently identified Cholic Acid (CA), a microbial bile acid that was increased in both patients and murine models with exercise, as a likely mediator of exercise induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 gene expression, supporting a stromal remodeling effect of physical activity.
In conclusion, this project demonstrates the role of host-intrinsic differences in regulation of exercise capacity, exercise-induced immune cell infiltration and activation, tumor growth, and stromal composition. Future work will evaluate the role of microbial metabolites such as CA as a biomarker of anti-tumor effect of exercise for patients with PDAC and as therapy for stromal remodeling to improve patient outcomes.
Recommended Citation
Pareek, Sumedha, "Host-intrinsic factors determine anti-tumor efficacy of exercise in pancreatic ductal adenocarcinoma" (2025). Dissertations & Theses (Open Access). 1501.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1501
Keywords
PDAC, Exercise, Pancreatic Cancer, CAFs, Tumor Infiltrating Immune Cells, Stroma, Exercise Capacity, Gut Microbiome, Cholic Acid, IL6
Included in
Animal Experimentation and Research Commons, Behavior and Behavior Mechanisms Commons, Biology Commons, Cancer Biology Commons, Exercise Science Commons, Immunity Commons, Medical Immunology Commons