Tumor-Reprogrammed Stromal BCAT1 Fuels Branched Chain Ketoacid Dependency in Stromal-Rich PDAC Tumors

Branched chain amino acids (BCAAs) supply 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, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumor milieu. Here we show distinct catabolic, oxidative, and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells and a marked branched chain ketoacid (BCKA)-reliance in PDAC cells in stroma-rich tumors. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β/SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumor microenvironment to supply amino acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with human patient-derived circulating tumor cells (CTCs) and PDAC tissue slices. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.