The role of branched-chain amino acid metabolism and hyperinsulinemia in pancreatic cancer

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Project Abstract Elevated levels of branched-chain amino acids (BCAAs) are associated with an increased risk of developing pancreatic ductal adenocarcinoma (PDA), a pancreatic cancer subtype making up over 90% of diagnoses. Increased plasma BCAAs are observed up to 10 years prior to diagnosis, but whether the elevation of these BCAAs directly contributes to PDA is not known. BCAAs are essential amino acids and their catabolism is orchestrated by the rate-limiting enzyme, the branched-chain keto-acid dehydrogenase (BCKDH) complex. However, whether the elevation of the BCAAs themselves in the plasma or their catabolism is responsible for PDA is not yet known. We have shown that acinar cells, the predominant cell population in the pancreas often responsible for PDA initiation, will preferentially use BCAAs over other substrates to produce acetyl-CoA. Acetyl- CoA is an important metabolite in energy production, epigenetic regulation, and the production of proteins, carbohydrates, and lipids. We showed that inhibiting acetyl-CoA production in these cells suppressed PDA initiation. Elevated BCAA levels have also been shown to increase insulin transcription and may lead to hyperinsulinemia. Insulin is a potent anabolic growth factor that increases pancreatic cancer growth rates. As insulin is produced in the pancreas, I hypothesize that this local insulin increase will aid PDA progression. This proposal aims to establish whether BCAAs have a causal role in PDA in both its initiation and its progression. I hypothesize that PDA initiation depends upon BCAAs as an energy source to promote ADM, while PDA progression is potentiated by elevated BCAA levels and hyperinsulinemia. To test the initiation hypothesis in Aim 1, I will cross our novel mouse model of pancreas-specific deletion of BCKDH to our murine model of PDA initiation. Rates of tumor initiation will be assessed through manipulation of the BCAA content in diet and through genetic ablation of BCAA catabolism. 13C labeling experiments will be done to assess metabolic utilization of BCAAs in the developing tumor to identify the mechanism by which acinar cells are using BCAAs for initiation. To test the progression hypothesis in Aim 2, mice will be provided with BCAA-enriched drinking water, which has been shown to lead to heightened tumor burden when implanted with established pancreatic cancer cell lines. The effect of increased insulin in these developing tumors will be assessed through genetic knockouts of the insulin receptor in the pancreatic cancer cells before implantation and by administration of pharmacological inhibitors. By assessing both tumor cell intrinsic insulin signaling and systemic effects of insulin level manipulation, I will be able to delineate whether PDA progression is caused by PDA cells directly or by other cell types in the tumor microenvironment and also whether BCAA catabolism directly impact either of these. The investigations in this project will provide a better understanding of BCAA metabolism and its contribution to hyperinsulinemia and identify vulnerabilities that can be exploited pharmacologically in patients with PDA.