Abstract PO-034: Increased physical activity delays development of obesity-induced pancreatic ductal adenocarcinoma in mice and modulates inflammation

Abstract

Abstract Background: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with no preventive strategies. Lifestyle interventions to decrease obesity might serve to prevent obesity-induced PDAC. We examined whether decreasing obesity via increased physical activity (PA) and/or diet-induced weight loss could prevent PDAC in mice and compared the levels of systemic inflammatory-associated cytokines in human subjects undergoing a PA intervention. Methods: Obesity-induced PDAC mouse models were exposed to various interventions before and after cancer initiation, that included increased PA, diet-induced weight loss, and/or chemotherapy. We evaluated body composition, tumor progression, growth, fibrosis, and inflammation. Circulating inflammatory-associated cytokines of overweight/obese human subjects before and after a PA intervention were also compared. Results: Genetically engineered PDAC mice on a PA intervention while on a HFD, gained less weight, displayed lower grade pancreatic intraepithelial neoplasias lesions, and fewer mice developed PDAC compared to controls. Similar results were observed in PDAC mice given a HFD to induce obesity, prior to a control diet (CD) and PA intervention, compared to mice given a CD after the HFD. PA alone or with a CD intervention decreased body weight but did not prevent tumor growth in an orthotopic mouse model of PDAC. PA combined with chemotherapy increased the percentage of splenic cluster of differentiation 8+ (CD8+) T cells in PDAC mice. Finally, PA prevented the increase of systemic inflammatory-associated cytokines in PDAC mice and in overweight/obese control human subjects. Conclusions: PA alone or with diet-induced weight loss delayed the progression of PDAC in genetically engineered mice and reduced inflammation. While these interventions did not prevent tumor growth in the orthotopic mouse model, it did modulate immune responses. Reducing obesity by increasing PA and decreasing dietary fat intake could be a way of reducing the incidence of PDAC in high-risk obese individuals. Citation Format: Valentina Pita-Grisanti, Kelly Dubay, Ali Lahooti, Niharika Badi, Olivia Ueltschi, Myrriah Chavez-Tomar, Samantha Terhorst, Sue Knoblaugh, Christopher Coss, Thomas Mace, Fouad Choueiry, Alice Hinton, Jennifer M Mitchell, Karen Basen-Engquist, Zobeida Cruz-Monserrate. Increased physical activity delays development of obesity-induced pancreatic ductal adenocarcinoma in mice and modulates inflammation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-034.