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Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours
Open accessAbstract
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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“Among these lysophosphatidylcholines are hydrolyzed by autotaxin released from cancer cells to provide the potent signaling molecule lysophosphatidic acid, which promotes PDAC proliferation and migration254”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [254]
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Metadata
- Authors
- Zhu, Z., Achreja, A., Meurs, N., Animasahun, O., Owen, S., Mittal, A., Parikh, P., Lo, T.-W., Franco-Barraza, J., Shi, J., Gunchick, V., Sherman, M. H., Cukierman, E., Pickering, A. M., Maitra, A., Sahai, V., Morgan, M. A., Nagrath, S., Lawrence, T. S., & Nagrath, D.
- Affiliations
- University of Michigan (US)
- Oregon Health & Science University (US)
- Fox Chase Cancer Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Nagrath, Deepak
- ORCID
- Venue
- Nature Metabolism
- Published
- 2020-07-06
- Volume
- 2
- Issue
- 8
- Pages
- 775-792
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC7438275
- OpenAlex
- W3040562565
- Cited by
- 204
- References
- 59
- Citations by year
- 2026: 31 · 2025: 36 · 2024: 37 · 2023: 34 · 2022: 33 · 2021: 27 · 2020: 6
- FWCI
- 9.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (K08 CA234222, R01CA208335, R01CA227622, R01CA222251, R01CA204969)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, branched-chain amino acids, branched-chain keto acids, BCAT1, cancer-associated fibroblasts, tumor stroma, TGF-beta, Smad5, extracellular matrix degradation, tumor microenvironment, cancer metabolism, circulating tumor cells
- MeSH terms
- Cancer-Associated Fibroblasts, Amino Acids, Branched-Chain, Transaminases, Energy Metabolism, Humans, Keto Acids, Oxidation-Reduction, Pancreatic Neoplasms, Tumor Stem Cell Assay, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Stromal Cells, Computational Biology, Carcinoma, Pancreatic Ductal, Smad5 Protein, Gene Knockdown Techniques
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