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.

胰腺癌是一种罕见但致死性的恶性肿瘤，其绝对死亡率位列所有癌症第四位。已知的危险因素包括肥胖、饮食与2型糖尿病，但由于该病发病率较低且上述因素间存在相互关联，难以单独分离各因素的影响。本研究通过对前瞻性人类队列开展流行病学分析，并在小鼠体内平行追踪胰腺癌的发生发展，以解析肥胖、饮食及糖尿病对胰腺癌的影响。通过对小鼠进行纵向监测与多组学分析，我们发现饮食中的蛋白质、糖类与脂肪成分具有截然不同的作用：饮食中的糖类可上调Mad2l1的表达并促进肿瘤增殖。通过对人类人群开展流行病学研究，我们发现饮食糖类会使携带MAD2L1特定基因型的人群胰腺癌易感风险显著升高。将上述研究结果转化至临床场景，将有助于筛选出胰腺癌高危人群以开展筛查，并有望将饮食干预作为潜在的治疗手段。