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

Zhu, Liang

Ji, Juntao

Ma, Jianjia

Wang, Dan

Liu, Muyun

Du, James Xianxing

Chen, Rong

Hou, Wei

Abbruzzese, James L

Logsdon, Craig D

Yang, Vincent W

Luo, Yongde

Lu, Weiqin

2022-12-01T21:03:41Z

2022-12-01T21:03:41Z

2022-05

2022-12-01T21:03:38Z

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.

cancers14112723

2072-6694

2072-6694

https://hdl.handle.net/10161/26302

eng

MDPI AG

Cancers

10.3390/cancers14112723

KRAS

high-carbohydrate diet

high-protein diet

inflammation

macronutrients

pancreatic cancer

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

Journal article

2723

11

Duke

School of Medicine

Clinical Science Departments

Institutes and Centers

Medicine

Medicine, Medical Oncology

Duke Cancer Institute

Published

14