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.

胰腺癌是一种罕见但致命的恶性肿瘤，其致死率在各类癌症中位居第四位。高致死率的核心诱因在于确诊时机偏晚，而这在一定程度上源于人们对其起始致病因素的认知尚不充分。目前已知的危险因素涵盖肥胖、饮食结构与2型糖尿病（type 2 diabetes），但由于该病发病率较低，且上述危险因素间存在相互关联，使得我们难以从患者数据中剥离出各因素的单独影响。本研究通过对前瞻性人类队列开展流行病学分析，并同步追踪小鼠体内的胰腺癌发生进程，以此解析肥胖、饮食与糖尿病对胰腺癌发生、发展及致死性的影响。通过对小鼠进行纵向磁共振成像（magnetic resonance imaging）与多组学（multi-omics）分析，本研究发现：肥胖以及饮食中蛋白质、糖类与脂肪的组成比例会对胰腺癌产生显著差异化影响，而糖尿病并未带来额外的影响。通过针对人类的流行病学研究，我们发现：膳食中的植物脂肪可降低未来胰腺癌的发病风险，而膳食糖类则会提升胰腺癌的易感性，且该效应呈现基因型依赖性。通过人类患者的遗传流行病学分析与小鼠模型的分子实验，本研究证实了MAD2L1与膳食葡萄糖在胰腺癌发病机制中存在相互作用。上述结果表明，无论是饮食的摄入量还是营养组成，均会影响小鼠与人类体内的胰腺癌进程。将这些研究结果转化至临床场景，将有助于识别需进行筛查的高危人群，并有望将饮食调整作为一种治疗手段。