Abstract C022: Exercise reduces pancreatic tumor in a gut microbiome dependent manner
Authors: Pareek Sumedha , Chandra Vidhi , Li Le , Patel Hetal , Lam Truong , LeRoux Olivereen , Liu Haoyue , Lee Jonghae , McAllister Florencia , Schadler Keri 
Published: November 2024

Abstract
Preclinical studies suggest that aerobic exercise influences the tumor microenvironment by normalizing vasculature and reducing immunosuppression in Pancreatic Ductal Adenocarcinoma (PDAC). Gut microbes can influence PDAC progression by modulating metabolic and immune pathways. However, a knowledge gap remains regarding the role of the gut microbiome in the anti-tumor effects of exercise. We hypothesized that the exercise-induced anti-tumor effect in PDAC is regulated by gut microbiome. We compared the effect of treadmill running on growth of orthotopic PDAC in C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), which have different microbiomes. Tumor-bearing mice performed treadmill exercise (ex, 12 meters/minute (m/min) for 45 minutes (min) daily) or were non-exercised controls (no-ex). Exercise reduced tumor weight compared to no-ex controls in Jax (no-ex, 0.72±0.05 grams (g); ex, 0.54±0.04g; p=0.04) but not in Tac mice (no-ex, 0.72±0.05g; ex, 0.78±0.05g; p=0.47). Interestingly, in Tac mice treated with antibiotics (ATBx) ad libitum, treadmill exercise reduced tumor growth (no-ex, 0.74±0.04 g; ex, 0.53±0.03g; p= 0.006). Taken together, this data indicates that the anti-tumor effect of exercise is affected by gut microbiome. We considered potential mechanisms by which exercise suppresses tumor growth. Tumor infiltrating immune cells were measured by flow cytometry and immunohistochemistry. No significant differences in the tumor infiltrating immune cells were observed between no-ex and ex mice from Tac or Jax, regardless of ATBx, indicating that gut microbiome mediated anti-tumor effect is independent of immune pathways. Previous studies have demonstrated that exercise reduces tumor growth in an intensity dependent manner. Therefore, to determine exercise intensity as percentage of Peak Velocity (VPeak), exercise capacity (ExCap) test was performed. VPeak (m/min), time to exhaustion (min), and distance to exhaustion (m) were used as indicators for treadmill ExCap. Treadmill ExCap was significantly lower in tumor bearing Tac mice (24.86±3.55m/min, 12.56±1.79min, 217.17±31.02m) compared to Jax mice (30.50±3.81m/min; 16.58±2.07min; 320.15±40.02m; p=0.01). However, ATBx treatment did not change the treadmill ExCap in the Tac mice (25.50±3.19m/min; 12.62±1.58min; 209.26±26.16m; p=0.97) despite significantly changing the effect of exercise on tumor growth, indicating that ExCap may not regulate differences observed in the tumor weight. Overall, these results indicate that gut microbiome regulates anti-tumor effects of exercise, that are independent of tumor infiltrating immune cells or exercise intensity. Analysis of serum and tumor metabolites, 16s rRNAseq to evaluate microbial differences, and bulk RNAseq on tumors, is underway with the goal of identifying microbial-derived metabolites which mediate the anti-tumor effect of exercise. Understanding how the gut microbiome mediates the efficacy of exercise to suppress tumor growth will be critical for maximizing the benefits of exercise for patients with PDAC.
Citation Format: Sumedha Pareek, Vidhi Chandra, Le Li, Hetal Patel, Truong Lam, Olivereen LeRoux, Haoyue Liu, Jonghae Lee, Florencia McAllister, Keri Schadler. Exercise reduces pancreatic tumor in a gut microbiome dependent manner [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C022.