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Zhu Z , Achreja A , Meurs N , Animasahun O , Owen S , Mittal A , Parikh P , Lo TW , Franco-Barraza J , Shi J , Gunchick V , Sherman MH , Cukierman E , Pickering AM , Maitra A , Sahai V , Morgan MA , Nagrath S , Lawrence TS , Nagrath D
Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours
Nat Metab. 2020 Aug;2(8) :775-792
PMID: 32694827    PMCID: PMC7438275    URL: https://www.ncbi.nlm.nih.gov/pubmed/32694827
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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.
2522-5812 Zhu, Ziwen Orcid: 0000-0002-6681-9153 Achreja, Abhinav Orcid: 0000-0002-1773-6490 Meurs, Noah Animasahun, Olamide Orcid: 0000-0002-4032-3619 Owen, Sarah Orcid: 0000-0002-4102-7707 Mittal, Anjali Parikh, Pooja Lo, Ting-Wen Orcid: 0000-0002-2127-2000 Franco-Barraza, Janusz Orcid: 0000-0003-3652-5311 Shi, Jiaqi Orcid: 0000-0003-4893-1587 Gunchick, Valerie Sherman, Mara H Cukierman, Edna Orcid: 0000-0002-1452-9576 Pickering, Andrew M Maitra, Anirban Orcid: 0000-0001-7923-9978 Sahai, Vaibhav Orcid: 0000-0003-1892-1548 Morgan, Meredith A Orcid: 0000-0001-7965-6878 Nagrath, Sunitha Orcid: 0000-0002-1497-7977 Lawrence, Theodore S Nagrath, Deepak Orcid: 0000-0002-8999-2282 R01CA227622/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ R21 CA231252/CA/NCI NIH HHS/United States K08 CA234222/CA/NCI NIH HHS/United States R01 CA232256/CA/NCI NIH HHS/United States R01 CA222251/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States R01CA204969/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ R01CA222251/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ R01CA208335/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ R01 CA227622/CA/NCI NIH HHS/United States Journal Article Germany Nat Metab. 2020 Jul 6. doi: 10.1038/s42255-020-0226-5.