Abstract LT009: Stromal BCAT1 drives branched-chain ketoacid dependency in stromal-rich PDAC tumours

Abstract

Abstract Branched chain amino acids (BCAAs) in cancer serve as requisite precursors for protein synthesis, maintaining metabolite pools in the tricarboxylic acid (TCA) cycle, and sustaining production of nucleotides and lipids. However, the role of stromal cancer associated fibroblasts (CAFs) in support of BCAA metabolism in tumors is still poorly understood. Since most studies in pancreatic cancers have focused on systemic or cancer cell autonomous BCAA metabolism, understanding cancer-stromal ecosystem requires insight into the intersection of cancer-associated transformations in the stroma with reprogramming of their BCAA metabolism. Deciphering the precise role of various cellular components in BCAA metabolism of tumors is complicated by conflicting evidence from past studies and the challenging nature of the intricate tumor microenvironment (TME). Neither systemic in vivo BCAA metabolism nor cancer cells’ BCAA metabolism alone is sufficient to dissect the stromal role. The difficulty in understanding BCAA metabolism in the tumor milieu is exacerbated by nutrient-scarcity, exchange reactions, and metabolite sharing between cancer and stromal cells. Both, the fibrotic environment and nutrient scarcity are difficult to mimic in aggressive murine PDAC models. The metabolic fates of the BCAAs, leucine, valine, and isoleucine, are cell- and tissue-dependent. BCAA transaminases (BCAT1/2), first deaminate BCAAs to branched chain a-ketoacids (BCKAs). The second step in BCAA metabolism involves irreversible BCKA oxidation catalyzed by the mitochondrial BCKA dehydrogenase (BCKDH) complex. Further, oxidation of BCKAs results in succinyl-CoA and acetyl-CoA that act as anaplerotic or ketogenic sources for the TCA cycle. Our recent study revealed differential BCAA metabolism in cancer and stromal compartments of PDAC tumors. We identified a strikingly higher BCAA catabolic flux in CAFs but increased BCKA oxidative flux in cancer cells. Further, CAF-secreted BCKAs were used for maintaining protein synthesis, augmenting TCA cycle metabolite pools, and increasing oxidative phosphorylation in cancer cells. To corroborate the mechanistic underpinnings discovered in our human CAF and cancer cell-line model, we employed two patient-derived models: circulating tumor cells (CTCs) and tumor slice cultures. Collectively, we elucidated an undiscovered metabolic-signaling crosstalk between PDAC and stromal cells and demonstrated that targeting BCAA metabolism in PDAC tumors could mitigate PDAC aggression. Ziwen Zhu, Abhinav Achreja, Noah Meurs, Olamide Animasahun, Sarah Owen, Anjali Mittal, Pooja Parikh, TingWen Lo, Janusz Franco-Barraza, Jiaqi Shi, Mara Sherman, Edna Cuikerman, Andrew Pickering, Anirban Maitra, Vaibhav Sahai, Meredith Morgan, Sunitha Nagrath, Thedore Lawrence, Deepak Nagrath, "Tumor Reprogrammed Stromal BCAT1 Fuels Branched Chain Ketoacid Dependency in Stromal-Rich PDAC Tumors", Nature Metabolism, 2 (8), 2020. Citation Format: Deepak Nagrath. Stromal BCAT1 drives branched-chain ketoacid dependency in stromal-rich PDAC tumours [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT009.