Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.

Nature Metabolism
Ziwen ZhuDeepak Nagrath

Abstract

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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Jul 23, 2020·Nature Metabolism·Russell E Ericksen, Weiping Han
Dec 30, 2020·Journal of Clinical Medicine·Pilar Espiau-RomeraPatricia Sancho
Feb 25, 2021·The Biochemical Journal·Megan C BlairZoltan Arany
Mar 7, 2021·Cancers·Teresa Gagliano, Claudio Brancolini
Jul 18, 2021·Nature Reviews. Cancer·Inmaculada Martínez-Reyes, Navdeep S Chandel
Jul 11, 2021·Nature Reviews. Cancer·Samuel A KerkCostas A Lyssiotis

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Datasets Mentioned

BETA
MCA1907
GSE36924
GSE62165
GSE93326

Methods Mentioned

BETA
RNA-seq
deamination
Fluorescence microscopy
fluorescence imaging
scanning electron microscopy
transfection
Chip
surgical resection
flow cytometry
Protein Assay

Software Mentioned

IsoCor
FreeVectors
Seahorse Analyzer
FlowJo
QuantStudio Design and Analysis
GraphPad Prism
R
Seurat

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