Abstract SY29-01: Role of nitrogen metabolism in obesity-associated pancreatic cancer

Abstract

Abstract Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDAC remain unknown. Here we show that obesity-driven PDAC exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDAC. In vivo infusion of 15N-glutamine in obese mouse models of PDAC demonstrates enhanced nitrogen flux into the urea cycle, and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDAC patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDAC on ARG2 rather than the principal hepatic ureagenic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer. Citation Format: Nada Y. Kalaany. Role of nitrogen metabolism in obesity-associated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY29-01.