TY - JOUR
T1 - Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours
AU - Zhu, Ziwen
AU - Achreja, Abhinav
AU - Meurs, Noah
AU - Animasahun, Olamide
AU - Owen, Sarah
AU - Mittal, Anjali
AU - Parikh, Pooja
AU - Lo, Ting Wen
AU - Franco-Barraza, Janusz
AU - Shi, Jiaqi
AU - Gunchick, Valerie
AU - Sherman, Mara H.
AU - Cukierman, Edna
AU - Pickering, Andrew M.
AU - Maitra, Anirban
AU - Sahai, Vaibhav
AU - Morgan, Meredith A.
AU - Nagrath, Sunitha
AU - Lawrence, Theodore S.
AU - Nagrath, Deepak
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs 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 tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. 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 tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.
AB - Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs 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 tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. 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 tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.
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U2 - 10.1038/s42255-020-0226-5
DO - 10.1038/s42255-020-0226-5
M3 - Article
C2 - 32694827
AN - SCOPUS:85087658126
SN - 2522-5812
VL - 2
SP - 775
EP - 792
JO - Nature Metabolism
JF - Nature Metabolism
IS - 8
ER -