Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease and oncogenic KRAS mutations are prevalent in PDAC patients. Oncogenic KRAS is critical for the initiation and development of PDAC; however, it alone is insufficient to drive pancreatic cancer. Oncogenic KRAS is an important mediator in metabolic reprogramming, including glucose, glutamine, and fatty acid metabolisms, for cancer cell survival, proliferation, and invasion. Oncogenic KRAS and chronic high-fat diet synergize to promote PDAC, suggesting that dietary intake is critically involved in PDAC development. Here, by feeding mice expressing an endogenous level of oncogenic KRAS(G12D) with a high-fat diet, high-carbohydrate diet, high-protein diet, or normal diet, we have demonstrated that different dietary macronutrients differentially impact pancreatic cancer susceptibility, and a high-protein diet may represent the desired, favorable dietary choice compared to high-fat diet and high-carbohydrate diet for pancreatic cancer patients. In addition, management of macronutrient intake aimed at thwarting inflammation is a promising preventive strategy for patients harboring oncogenic KRAS. ABSTRACT: KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRAS(G12D) specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in Kras(G12D/+) mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in Kras(G12D/+) mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.