Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation

Abstract

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice. METHODS: Circulating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated. RESULTS: PA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth. CONCLUSIONS: PA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals. KEYWORDS: Obesity, voluntary wheel running, weight loss, diet intervention, high-risk PDAC

Decoding the obesity–cancer connection: lessons from preclinical models of pancreatic adenocarcinoma

“…Obese mice exhibit lower physical activity, and it remains unclear how much of the tumor-promoting phenotype of obesity could be attributed to a more sedentary nature. Therefore, whether and how increased physical activity impedes tumorigenesis in obese mice remains to be elucidated, though newer studies are exploring these relationships ( Pita-Grisanti et al, 2023 Preprint ). Despite the plethora of intrinsic (e.g., sex, genetic mutations, strain) and environmental (e.g., HFD amount and composition, physical activity intervention) variables that could confound results, the totality of preclinical studies to date support the conclusion that obesity—mediated both by how much and what is eaten—is a causal risk factor in PDAC development and provide critical in vivo models to uncover mechanisms of obesity-driven cancer.…”

“…Furthermore, there remains a dearth of studies examining putative mechanisms in early tumorigenesis, including (1) obesity-driven alterations in pre-tumor cell metabolism; (2) the range of pathogenic obesity-associated endocrine hormones, how they are induced, and how they stimulate tumorigenesis; (3) the precise cellular and molecular mechanisms by which obesity-induced inflammation drives tumor initiation and modulates anti-tumor immunity; and (4) whether and how obesity-associated microbial dysbiosis contributes to PDAC pathogenesis. Fortunately, the capacity to address these questions is being enabled by emerging isocaloric diet panels ( Hu et al, 2018 ) and further advances in GEMMs and organoid transplant modeling ( Tuveson & Clevers, 2019 ; Tuveson, 2021 ), such as reversible obesity models ( Chung et al, 2020 ), defined mouse exercise paradigms ( Kurz et al, 2022 ; Pita-Grisanti et al, 2023 Preprint ), lineage-tracing of tumor progression ( Rhim et al, 2012 ; Muzumdar et al, 2016 ), inducible neoantigen induction to study antigen-specific T cell responses in vivo ( Damo et al, 2020 ; Freed-Pastor et al, 2021 ), and more sophisticated techniques to manipulate and analyze microbial communities ( Chen et al, 2019 ; Han et al, 2021 ). With unbiased methods for epigenomic, transcriptomic, proteomic, and metabolomic analyses that now exist and increased funding from major organizations (Grand Challenges, National Cancer Institute, etc.…”