BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma

Jin-Tao Li; Miao Yin; Di Wang; Jian Wang; Ming-Zhu Lei; Ye Zhang; Ying Liu; Lei Zhang; Shao-Wu Zou; Li-Peng Hu; Zhi-Gang Zhang; Yi-Ping Wang; Wen-Yu Wen; Hao-Jie Lu; Zheng-Jun Chen; Dan Su; Qun-Ying Lei

doi:10.1038/s41556-019-0455-6

BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma

Nat Cell Biol. 2020 Feb;22(2):167-174. doi: 10.1038/s41556-019-0455-6. Epub 2020 Feb 6.

Authors

Jin-Tao Li^#^{1

2}, Miao Yin^#^{1

2}, Di Wang^#^{1

2}, Jian Wang^{1

2}, Ming-Zhu Lei^{1

2}, Ye Zhang³, Ying Liu⁴, Lei Zhang⁵, Shao-Wu Zou⁶, Li-Peng Hu⁷, Zhi-Gang Zhang⁷, Yi-Ping Wang^{1

2}, Wen-Yu Wen⁵, Hao-Jie Lu⁵, Zheng-Jun Chen⁸, Dan Su⁹, Qun-Ying Lei^{10

11

12}

Affiliations

¹ Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Key Laboratory of Cancer Proteomics of National Health Commission, XiangYa Hospital, Central South University, Changsha, China.
⁴ Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁵ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁶ Department of Hepatopancreatobiliary Surgery, Shanghai Tenth People's Hospital, Tong Ji University, Shanghai, China.
⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁸ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
⁹ Cancer Research Institute, Zhejiang Cancer Hospital and Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, China.
¹⁰ Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. qlei@fudan.edu.cn.
¹¹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. qlei@fudan.edu.cn.
¹² State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. qlei@fudan.edu.cn.

^# Contributed equally.

PMID: 32029896
DOI: 10.1038/s41556-019-0455-6

Abstract

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)^1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC^3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-Kras^G12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Adult
Amino Acids, Branched-Chain / metabolism*
Amino Acids, Branched-Chain / pharmacology
Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology
Carcinoma, Pancreatic Ductal / genetics*
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Disease Progression
Female
Gene Expression Regulation, Neoplastic*
Heterografts
Humans
Isoenzymes / genetics
Isoenzymes / metabolism
Keto Acids / metabolism
Keto Acids / pharmacology
Male
Mice
Mice, Transgenic
Middle Aged
Minor Histocompatibility Antigens / genetics*
Minor Histocompatibility Antigens / metabolism
Organoids / drug effects
Organoids / metabolism
Organoids / pathology
Pancreatic Ducts / drug effects
Pancreatic Ducts / metabolism
Pancreatic Ducts / pathology
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Pregnancy Proteins / genetics*
Pregnancy Proteins / metabolism
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism
Signal Transduction
Syk Kinase / genetics
Syk Kinase / metabolism
Transaminases / genetics*
Transaminases / metabolism

Substances

Amino Acids, Branched-Chain
Isoenzymes
KRAS protein, human
Keto Acids
Minor Histocompatibility Antigens
Pregnancy Proteins
Ribonucleoproteins
SS-A antigen
Transaminases
BCAT2 protein, human
SYK protein, human
Syk Kinase
Proto-Oncogene Proteins p21(ras)