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 - Funding Information:
We thank and are grateful to three anonymous reviewers and editors for their incisive comments and several excellent suggestions. D.N. is supported by grants from NCI R01CA227622, R01CA222251 and R01CA204969. DN is also supported by Rogel Cancer Center grant. J.S. is supported by grant from NCI K08 CA234222. EC is funded by NCI grants R21CA231252 and R01CA232256, Core Grant CA06927. This work was supported in part by grants from NCI R01CA208335 to S.N. Z.Z. and A.A. are supported by the University of Michigan Precision Health Scholars Awards. Flow cytometry experiments were performed in the Flow Cytometry Research Core at the University of Michigan, Biomedical Research Core Facilities (BRCF). Confocal microscopy was performed in the Microscopy and Image-analysis Laboratory (MIL) at the University of Michigan, Biomedical Research Core Facilities (BRCF). Scanning electron microscopy was performed at the Michigan Center for Materials Characterization (MC2) at University of Michigan which is supported by the University of Michigan College of Engineering and NSF grant DMR-0320740.
Funding Information:
A. Maitra receives royalties from Cosmos Wisdom Biotechnologies for a license related to a biomarker test for pancreatic cancer early detection. V.S. is a consultant at Halozyme, QED, Ipsen and Incyte. V.S. receives funding from Celgene, Bristol-Myers Squibb, Agios, Incyte, Clovis Oncology, Debiopharm Group, FibroGen, Halozyme, MedImmune, Rafael Pharmaceuticals and Ipsen. M.A.M. receives honoraria from AstraZeneca. S.N. is the named inventor on a patent for Microfluidic Labyrinth Technology granted to the University of Michigan. S.N. is a cofounders of Labyrinth Biotech. The funders and the company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85087658126&partnerID=8YFLogxK
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 -