依赖LKB1调节的TPI1在人和小鼠肺腺癌之间产生的代谢差异

SCI 21 February 2023

LKB1-dependent regulation of TPI1 creates a divergent metabolic liability between human and mouse lung adenocarcinoma

(Cancer Discovery, IF: 38.272)

Benjamin D. Stein, John R. Ferrarone, Eric E. Gardner, Jae Won Chang, David Wu, Pablo E. Hollstein, Roger J. Liang, Min Yuan, Qiuying Chen, John S. Coukos, Miriam Sindelar, Bryan Ngo, Steven S. Gross, Reuben J. Shaw, Chen Zhang, John M. Asara, Raymond E. Moellering, Harold Varmus, Lewis C. Cantley

CORRESPINDENCE TO: bds2005@med.cornell.edu, varmus@med.cornell.edu, lewis_cantley@dfci.harvard.edu

ABSTRACT 摘要   

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD) and activating mutations frequently co-occur with loss-of-function mutations in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered co-mutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the Salt Inducible Kinases (SIKs) in an LKB1-dependent manner, modulating flux between completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue which can be oxidized to alter TPI1 activity without a need for SIKs or LKB1. Our findings suggest this metabolic flexibility is critical in rapidly growing cells with KRAS and TP53 mutations, explaining why loss of LKB1 creates a liability in these tumors.

KRAS是人肺腺癌（hLUAD）中最常见的突变癌基因，激活突变经常与TP53或STK11/LKB1中的功能丧失突变共同发生。然而，在hLUAD中很少观察到所有三种基因的突变，即使工程化的共突变在小鼠肺腺癌（mLUAD）中具有高度侵袭性。在这里，我们通过揭示磷酸丙糖异构酶（TPI1）调控的进化差异，为这种差异提供了机械解释。在hLUAD中，TPI1活性通过盐诱导激酶（SIK）在Ser21处的磷酸化以LKB1依赖性方式调节，调节糖酵解完成和甘油脂质产生之间的通量。在小鼠中，TPI1的Ser21是Cys残基，其可以被氧化以改变TPI1活性而不需要SIK或LKB1。我们的发现表明，这种代谢灵活性对于具有KRAS和TP53突变的快速生长的细胞至关重要，这解释了为什么LKB1的缺失会在这些肿瘤中造成负担。

STATEMENT OF SIGNIFICANCE 意义陈述  

Utilizing phospho-proteomics and metabolomics in genetically engineered human cell-lines and GEMMs we uncover an evolutionary divergence in metabolic regulation within a clinically relevant genotype of human LUAD with therapeutic implications. Our data provide a cautionary example of the limits of GEMMs as tools to study human diseases such as cancers.

在基因工程人类细胞系和GEMM中利用磷酸化蛋白质组学和代谢组学，我们揭示了具有治疗意义的人类LUAD临床相关基因型内代谢调节的进化差异。我们的数据提供了GEMM作为研究人类疾病（如癌症）工具的局限性的警示性例子。

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