Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2 |
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| Enthalten in: |
Nature metabolism - 2(2020), 8 vom: 21. Aug., Seite 775-792 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Ziwen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.12.2020 Date Revised 18.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42255-020-0226-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312710224 |
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| 100 | 1 | |a Zhu, Ziwen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 31.12.2020 | ||
| 500 | |a Date Revised 18.02.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Amino Acids, Branched-Chain |2 NLM | |
| 650 | 7 | |a Keto Acids |2 NLM | |
| 650 | 7 | |a SMAD5 protein, human |2 NLM | |
| 650 | 7 | |a Smad5 Protein |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
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| 700 | 1 | |a Achreja, Abhinav |e verfasserin |4 aut | |
| 700 | 1 | |a Meurs, Noah |e verfasserin |4 aut | |
| 700 | 1 | |a Animasahun, Olamide |e verfasserin |4 aut | |
| 700 | 1 | |a Owen, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Mittal, Anjali |e verfasserin |4 aut | |
| 700 | 1 | |a Parikh, Pooja |e verfasserin |4 aut | |
| 700 | 1 | |a Lo, Ting-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Franco-Barraza, Janusz |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Jiaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Gunchick, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Sherman, Mara H |e verfasserin |4 aut | |
| 700 | 1 | |a Cukierman, Edna |e verfasserin |4 aut | |
| 700 | 1 | |a Pickering, Andrew M |e verfasserin |4 aut | |
| 700 | 1 | |a Maitra, Anirban |e verfasserin |4 aut | |
| 700 | 1 | |a Sahai, Vaibhav |e verfasserin |4 aut | |
| 700 | 1 | |a Morgan, Meredith A |e verfasserin |4 aut | |
| 700 | 1 | |a Nagrath, Sunitha |e verfasserin |4 aut | |
| 700 | 1 | |a Lawrence, Theodore S |e verfasserin |4 aut | |
| 700 | 1 | |a Nagrath, Deepak |e verfasserin |4 aut | |
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