Host-intrinsic factors determine anti-tumor efficacy of exercise in pancreatic ductal adenocarcinoma

<p>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.</p> <p>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.</p> <p>We interrogated tumor stromal composition changes with exercise and observed a gut microbiome dependent reduction in alpha smooth muscle actin (αSMA⁺) cells and <em>Il6</em> 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 <em>IL6</em> gene expression, supporting a stromal remodeling effect of physical activity.</p> <p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Pareek, Sumedha
• <h2>0000-0001-6492-3849</h2>

Contributors dc:contributor

• Keri Schadler
• Florencia McAllister
• Seyed Javad Moghaddam

• PDAC
• Exercise
• Pancreatic Cancer
• CAFs
• Tumor Infiltrating Immune Cells
• Stroma
• Exercise Capacity
• Gut Microbiome
• Cholic Acid
• IL6
• Animal Experimentation and Research
• Behavior and Behavior Mechanisms
• Biology
• Cancer Biology
• Exercise Science
• Immunity
• Medical Immunology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1501

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2558