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 PDAC3,4. 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-KrasG12D/+; 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.

中文翻译：

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BCAT2介导的BCAA分解代谢对于胰腺导管腺癌的发展至关重要。

支链氨基酸（BCAA）的代谢可能与胰腺导管腺癌（PDAC）1-4的发展有关。BCAA转氨酶2（BCAT2）对于PDAC中苹果酸酶的缺失所带来的附带致死性至关重要，而BCAA-BCAT代谢途径促成了除PDAC3,4以外的非小细胞肺癌（NSCLC）。但是，底层机制仍未定义。在这里，我们揭示了BCAT2在小鼠模型和人类PDAC中升高。此外，在LSL-KrasG12D / +中，胰腺组织特异性敲除Bcat2会阻碍胰腺上皮内瘤变（PanIN）的进展。Pdx1-Cre（KC）小鼠。在功能上，BCAT2增强BCAA摄取，以维持BCAA分解代谢和线粒体呼吸。值得注意的是，BCAA以剂量依赖性方式增强了KC小鼠的胰管类器官的生长，而添加支链α-酮酸（BCKA）和核碱基可挽救被BCAT2抑制剂抑制的KC类器官的生长。此外，KRAS可以稳定BCAT2，BCAT2由脾酪氨酸激酶（SYK）和E3连接酶含三重基序的蛋白21（TRIM21）介导。此外，BCAT2抑制剂可改善KC小鼠的PanIN形成。值得注意的是，较低的BCAA饮食也会阻碍PDAC小鼠模型中PDAC的发展。因此，BCAT2介导的BCAA分解代谢对于具有KRAS突变的PDAC的发展至关重要。靶向BCAT2或降低饮食中的BCAA可能具有翻译意义。它是由脾酪氨酸激酶（SYK）和E3连接酶含三重基序的蛋白21（TRIM21）介导的。此外，BCAT2抑制剂可改善KC小鼠的PanIN形成。值得注意的是，较低的BCAA饮食也会阻碍PDAC小鼠模型中PDAC的发展。因此，BCAT2介导的BCAA分解代谢对于具有KRAS突变的PDAC的发展至关重要。靶向BCAT2或降低饮食中的BCAA可能具有翻译意义。它是由脾酪氨酸激酶（SYK）和E3连接酶含三重基序的蛋白21（TRIM21）介导的。此外，BCAT2抑制剂可改善KC小鼠的PanIN形成。值得注意的是，较低的BCAA饮食也会阻碍PDAC小鼠模型中PDAC的发展。因此，BCAT2介导的BCAA分解代谢对于具有KRAS突变的PDAC的发展至关重要。靶向BCAT2或降低饮食中的BCAA可能具有翻译意义。