Abstract PR015: Excess dietary oleic acid primes the pancreas for cancer
Authors: Ruiz Christian F. , McDonnell Rylee , Kaplan Jennifer , de Jong Jasper , Shugrue Christine , Rudolph Michael C. , Gorelick Fred S. , Wysolmerski John , Rodeheffer Matthew , Muzumdar Mandar D. 
Published: November 2022

Abstract
Human epidemiologic studies support a strong link between increased pancreatic adenocarcinoma (PDAC) risk and high fat diet (HFD) consumption, obesity, and overall energy imbalance. Given the rapid rise in worldwide obesity rates and the prevalence of western diets rich in fat, deciphering these mechanisms is not only a societal imperative but also represents a key untapped target to develop novel strategies for prevention and therapy. The translational relevance of diet research, however, has been limited by inconsistencies in fat source and consumption across human populations and mouse studies. Therefore, whether and how specific dietary fatty acids drive cancer development is poorly understood. To identify commonly consumed dietary fats capable of promoting pancreatic tumorigenesis, we fed a novel panel of 12 isocaloric HFDs – differing solely in fat source and representing the diversity of modern human fat consumption (as per statistics from the USDA) – to an oncogenic Kras-driven mouse model (KC: Pdx1-Cre; KrasLSL-G12D/+) that closely mimics the genetic and histologic features of human PDAC progression. Surprisingly, we found that diets rich in oleic acid (OA), a monounsaturated fat typically associated with good health, were strongly correlated with enhanced precancerous pancreatic intraepithelial neoplasia (PanIN) formation, arguing that OA enhances Kras-induced cellular transformation and early progression. High-oleic diets (HODs) and OA treatment of primary acinar cells induced loss of acinar cell identity and acquisition of ductal markers, consistent with a direct role for OA in acinar-to-ductal metaplasia (ADM), a prerequisite step in early PDAC development. Lipidomic analyses of plasma, liver, and muscle of mice fed HODs revealed greater circulating OA levels and increased tissue incorporation of OA into the acyl chains of phospholipids and sphingolipids, which make up the plasma membrane of cells and mediate intracellular and extracellular signaling. Furthermore, plasma and tissue OA levels more strongly correlated with tumor development, suggesting that direct OA pancreatic tissue incorporation could drive tumorigenesis. Indeed, molecular and biochemical analyses confirmed upregulation in the expression of de novo lipogenesis genes, alterations in lipid metabolism, and enhanced mTOR signaling in pancreata of mice fed HODs. Overall, these results directly link dietary OA to pancreatic lipid metabolism and transformation during PDAC development and highlight the complex pleiotropic effects of dietary fatty acids on health and disease: OA, while beneficial for heart health, may promote the development of certain cancers, such as PDAC. Uncovering the links between specific dietary fats and tumorigenesis are critical to enable precision nutritional guidance for the prevention and treatment of PDAC and potentially other obesity-associated cancers.
Citation Format: Christian F. Ruiz, Rylee McDonnell, Jennifer Kaplan, Jasper de Jong, Christine Shugrue, Michael C. Rudolph, Fred S. Gorelick, John Wysolmerski, Matthew Rodeheffer, Mandar D. Muzumdar. Excess dietary oleic acid primes the pancreas for cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR015.