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

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. 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. 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. Through longitudinal monitoring and multi-omics analysis in mice we found distinct effects of protein, sugar and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we dietary sugars gave a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. Translation of these results to a clinical setting could aid identification of the at-risk population for screening and potential harness dietary modification as a therapeutic measure.