Abstract 2184: A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism

Abstract Increased adiposity represents a modifiable risk factor of pancreatic cancer. Multiple preclinical studies have shown that a high-fat and high-sugar diets on the acceleration of pancreatic carcinogenesis, in the context of obesity. However, the impact of diets resembling the omega-6 to omega-3 fatty acid (FA) ratio in a Western-style diet, remains unclear. Furthermore, the role of the mesenteric adipose tissue (MAT) in pancreatic carcinogenesis is poorly characterized. Thus, we aimed to determine the impact of a high-fat diet with a ratio of 9 parts omega-6 FA to each omega-3 FA, on early stages of pancreatic carcinogenesis in a genetically engineered LSL- KrasLSL-G12D; Ptf1aCre/+ (KC) model of pancreatic cancer, with an emphasis on evaluating the contribution of the MAT within the pancreatic microenvironment. For this purpose, cohorts of male and female KC mice (6-8 males and females per diet group) were randomly assigned to either a control diet (CD) group (9:1 of omega-6 FAs to omega-3 FAs) or a high-fat diet (HFD) group (9:1 of omega-6 FAs to omega-3 FAs) and fed their respective diets until three months of age. After eight weeks on their diets, HFD-fed mice had significantly increased body weight, fat mass, and elevated serum leptin levels. Furthermore, HFD-fed mice had increased acinar-to-ductal metaplasia, associated with increased PCNA expression, ERK and STAT3 phosphorylation and elevated pro-tumorigenic immune cell expression compared to CD-fed mice. Although no significant differences in MAT weight or adipocyte size were observed after 8 weeks between the groups, metabolomics analysis of the MAT revealed that HFD-fed mice had significant upregulation of many key metabolites linked to proliferative and inflammatory pathways. For instance, HFD-fed female KC mice had significant differences in α-linolenic acid metabolism and the biosynthesis of unsaturated fatty acids, while male mice had significant differences in arginine biosynthesis, amino acid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism. HFD-fed female mice had a significant increase in α-linolenic acid and linoleic acid in MAT, concurrent with a reduction in inosine 5-monophosphate and α-tocopherol compared to female CD-fed mice. HFD-fed male mice displayed a more pronounced difference in metabolites, including an increase in α-linolenic acid, linoleic acid, malic acid, glutamine, isoleucine, and several other amino acids, with a concurrent reduction in lauric acid and palmitoleic acid compared to male CD-fed mice. In summary, a HFD accelerates pancreatic carcinogenesis through multifaceted mechanisms, including effects on the tumor and surrounding adipose depots. A HFD increases affects MAT metabolism in a sex-dependent manner, that might ultimately promote early-stage progression of pancreatic carcinogenesis. Citation Format: Aya Ead, Joanna Wirkus, Gerardo G. Mackenzie. A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2184.