Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

Cell Rep. 2020 Jul 14;32(2):107880. doi: 10.1016/j.celrep.2020.107880.

Abstract

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 effects 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 find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure.

Keywords: EPIC; MAD2L1; diet; dietary fat; dietary sugar; epidemiology; gene-environment interaction; genetics; mouse model; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Cycle
  • Diet*
  • Dietary Carbohydrates
  • Dietary Fats
  • Dietary Proteins
  • Disease Susceptibility*
  • Energy Intake*
  • Female
  • Gene-Environment Interaction
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Nutritional Physiological Phenomena*
  • Obesity
  • Pancreatic Neoplasms / pathology*

Substances

  • Dietary Carbohydrates
  • Dietary Fats
  • Dietary Proteins