Abstract IA26: Identifying metabolic liabilities in obesity-associated pancreatic cancer

Obesity is a rising pandemic that is increasingly being recognized for its striking correlation with the incidence of/mortality from cancers of different tissues, particularly that of the pancreas. Ranking as the fourth leading cause of cancer death in the United States, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal, insidious malignancy whose poor prognosis is reflected in a 5-year survival rate of only 5%. In an obese state characterized by elevated circulating levels of insulin and insulin-like growth factor-1 (IGF-1), metabolic signaling pathways, including PI3K/Akt might be aberrantly regulated, altering tumor cell metabolism and driving the maintenance of PDAC. Recognized as a hallmark of cancer formation, altered cellular metabolism is evident in Kras-driven PDAC tumors. However, the specific metabolic impact of obesity and increased insulin and IGF-1 levels on PDAC tumors has not been thoroughly investigated. We performed a large orthotopic xenograft experiment involving the injection of human pancreatic cancer cells modified to either express constitutively active, myristoylated Akt, or a control fluorescent protein (CFP) into the pancreata of lean or diet-induced obese immunodeficient mice. We find that control CFP-tumors grown in obese mice and all Akt-tumors, independent of obesity, are significantly larger than CFP-tumors grown in lean mice. Gene expression and metabolomics analyses demonstrate a striking representation of distinct metabolic pathways, including the nitrogen/arginine or urea cycle pathway in pancreatic tumors grown in obese versus lean mice. This pathway enrichment partially overlaps with that observed in the Akt-driven tumors, independent of obesity. Here we describe the validation of these results by altering urea cycle gene expression in the human PDAC cells and assessing their effect on PDAC cell proliferation, survival, metabolism, and response to arginine deprivation both in tissue culture in vitro and as orthotopic xenografts in the pancreata of lean or diet-induced obese mice in vivo. These studies will help identify metabolic dependencies in Akt-driven or non-Akt-driven pancreatic tumors grown under either obese/hyperinsulinemic or lean states, that could be targeted therapeutically in PDAC patients. Citation Format: Tamara Zaytouni, Cory Dubois, Daniel Hitchcock, Nicholas Stylopoulos, Clary Clish, Nada Kalaany. Identifying metabolic liabilities in obesity-associated pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA26.