Abstract A065: A Western-style mimicking high-fat diet increases early stage pancreatic carcinogenesis in a KC murine model

Abstract

Abstract Background: Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the USA. Given the limited clinical benefit of current treatments, pancreatic cancer prevention appears as a key approach to lowering the mortality and suffering caused by this disease. A key modifiable risk factor for pancreatic cancer is the diet. Previous studies have indicated that high fat diets, but also high sugar diets, accelerate pancreatic carcinogenesis. Although the link between increased body fatness and pancreatic cancer risk is apparent, the specific role played by the different dietary fats remains unclear. Moreover, the impact of only diets rich in fats with an omega-6 to omega-3 fatty acid (FA) ratio resembling that of a Western-style diet, remains unclear. Objective: To determine the impact of a high fat diet, that mimics the Western-style diet with a ratio of about 10 parts of omega-6 FA to each omega-3 FA, on early stages of pancreatic carcinogenesis in a clinically relevant, genetically engineered LSL- KrasLSL-G12D; Ptf1aCre/+ (KC) model of pancreatic cancer. Methods: Cohorts of male and female KC mice (N= 44; 10-12 males and females per diet group) were weaned at three weeks of age, single housed, and placed on the AIN93G diet for two weeks. At five weeks of age, the KC mice were randomly assigned to either a control diet (CD) group (12% calories from fat with an omega-6:omega-3 FA ratio of 10:1) or a diet induced obesity (DIO) group (60% calories from fat with an omega-6:omega-3 FA ratio of 10:1) and fed their respective diets until three months of age. Mice were euthanized and organs and serum were collected for further analysis. Results: After 7 weeks on their respective diets, DIO-fed mice had higher body weight compared to CD-fed mice; however, it only reached statistically significance in female mice. Male and female DIO-fed mice had significantly higher fat mass, and significantly lower lean, compared to CD-fed mice. Additionally, male, but not female, DIO-fed mice had a significantly larger pancreas’ weight compared to CD-fed mice. Moreover, upon histological analysis, DIO-fed mice had a significantly increased rate of acinar-to-ductal metaplasia, compared to CD-fed mice. In addition, there were high serum concentrations of leptin, insulin as well as the pro-inflammatory cytokines IL-6, and TNF-α in KC mice fed a DIO compared to the CD-fed mice. In contrast, no differences were noted in MCP-1 and IL-1β between groups. Conclusion: Our results indicate that feeding a high-fat diet (mimicking a Western-style diet) for 7 weeks leads to increased body fatness, acinar-to-ductal metaplasia, and increased levels of leptin, insulin and pro-inflammatory cytokines. Current work is underway to characterize the cellular mechanisms on how DIO induces pancreatic carcinogenesis, as well as the specific roles played by select FA in pancreatic carcinogenesis. Citation Format: Aya Ead, Joanna Wirkus, Gerardo G. Mackenzie. A Western-style mimicking high-fat diet increases early stage pancreatic carcinogenesis in a KC murine model [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 A065.