Targeting Branched Chain Amino Acid Metabolism in Tumor Microenvironment

Abstract

Branched Chain amino acids (BCAAs) play an essential role in cell metabolism supplying both carbon and nitrogen in pancreatic cancers, and their increased levels have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumor milieu. In chapter 1, we present an overview of PDAC biology, tumor microenvironment (TME), altered cancer metabolism and BCAA metabolism. In chapter 2, we uncover differential gene expression of enzymes involved in BCAA metabolism accompanied by distinct catabolic, oxidative, and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells with a marked branched-chain keto acids (BCKA)-addiction in PDAC cells. In chapter 3, we showed that cancer-induced stromal reprogramming fuels this BCKA-addiction. We then show the functions of BCAT2 and DBT in the PDAC cells in chapters 3 and 4. We identify BCAT1 as the BCKA regulator in CAFs in chapter 5. In chapter 6, we dictated the internalization of the extracellular matrix from the tumor microenvironment to supply amino acid precursors for BCKA secretion by CAFs. We also showed that the TGF-β/SMAD5 axis directly targets BCAT1 in CAFs in chapter 7. In chapter 8, we validate the in vitro results in human patient-derived circulating tumor cells (CTCs) model. Furthermore, the same results were also validated in PDAC tissue slices, which recapitulate tumor heterogeneity and mimic the in vivo microenvironment in chapter 9. We conclude this manuscript with chapter 10 in which we propose future studies and present directions towards pancreatic cancer research. In summary, our findings reveal therapeutically actionable targets in stromal and cancer cells to regulate the symbiotic BCAA coupling among the cellular constituents of the PDAC microenvironment.