Heterogeneous effects of calorie content and nutritional components underlie dietary influence over pancreatic cancer susceptibility in mice and humans. Heterogeneous effects of calorie content and nutritional components underlie dietary influence over pancreatic cancer susceptibility in mice and humans

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. The main reason for the high mortality is late detection, caused in part by an incomplete understanding of the initiating factors. Known risk factors include obesity, diet and type 2 diabetes, however the low incidence rate and interconnection of these factors confound the isolation of individual effects from patient data. Here we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the impacts of obesity, diet and diabetes on pancreatic cancer development, growth and lethality. Through longitudinal magnetic resonance imaging and multi-omics analysis in mice we found distinct effects of obesity and the protein, sugar and fat composition of diet, and no added impact of diabetes. Using epidemiological approaches in humans, we found that dietary plant fats reduced the risk of future pancreatic cancer development, while dietary sugars gave a genotype-dependent increased susceptibility to pancreatic cancer. An interaction between MAD2L1 and dietary glucose in pancreatic cancer pathogenesis was supported through both genetic epidemiology in human patients and molecular analysis of mouse models. These results demonstrate that both quantitative and qualitative dietary effects are at play in pancreatic cancer kinetics, in both mice and humans. Translation of these results to a clinical setting could aid identification of theat-risk population for screening and potential harness dietary modification as a therapeutic measure.