LKB1对TPI1的依赖性调控在人类和小鼠肺腺癌之间产生了不同的代谢责任

2023-03-24 10:09

利用遗传工程人类细胞系和遗传工程小鼠模型（GEMM）中的磷蛋白组学和代谢组学，我们发现在人类LUAD的临床相关基因型中，代谢调节的进化差异具有治疗意义。

SCI 23 March 2023

LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma

(Cancer Discov IF: 39.4)

Corresponding Authors: Lewis C. Cantley, Dana-Farber Cancer Institute, 450 Brookline Avenue, Smith Building, Room 970, Boston, MA 02215-5450. Phone: 617-632-5034; E-mail: lewis_cantley@dfci.harvard.edu; Benjamin D. Stein, Weill Cornell Medicine, 413 East 69th Street, BB750, New York, NY 10021. Phone: 646-962-6333; E-mail: bds2005@med.cornell.edu; and Harold Varmus, Weill Cornell Medicine, 413 East 69th Street, BB1322, New York, NY 10021. Phone: 646-962-7254; E-mail: varmus@med.cornell.edu Cancer Discov 2023;13:1–24 doi: 10.1158/2159-8290.CD-22-0805

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 muta- tions in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered comutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here, we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in the regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphoryla- tion at Ser21 by the salt inducible kinases (SIK) in an LKB1-dependent manner, modulating flux between the completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue that 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 the loss of LKB1 creates a liability in these tumors.

KRAS是人类肺腺癌（hLUAD）中最经常突变的致癌基因，激活性突变经常与TP53或STK11/LKB1的功能丧失性突变同时发生。然而，在hLUAD中很少观察到这三个基因的突变，尽管工程突变在小鼠肺腺癌（mLUAD）中具有高度的侵略性。在这里，我们通过发现三磷酸腺苷异构酶（TPI1）调控的进化分歧，为这一差异提供了机制上的解释。在hLUAD中，TPI1的活性通过盐诱导性激酶（SIK）以LKB1依赖的方式在Ser21处进行磷酸化调节，调节糖酵解的完成和甘油脂的产生之间的通量。在小鼠中，TPI1的Ser21是一个Cys残基，可以被氧化以改变TPI1的活性而不需要SIKs或LKB1。我们的研究结果表明，这种代谢灵活性在具有KRAS和TP53突变的快速生长的细胞中是至关重要的，解释了为什么LKB1的丢失会在这些肿瘤中产生一种责任。

SIGNIFICANCE 意义

Utilizing phosphoproteomics and metabolomics in genetically engineered human cell lines and genetically engineered mouse models (GEMM), we uncover an evolutionary divergence in metabolic regulation within a clinically relevant genotype of human LUAD with therapeutic implica- tions. Our data provide a cautionary example of the limits of GEMMs as tools to study human diseases such as cancers.

利用遗传工程人类细胞系和遗传工程小鼠模型（GEMM）中的磷蛋白组学和代谢组学，我们发现在人类LUAD的临床相关基因型中，代谢调节的进化差异具有治疗意义。我们的数据提供了一个警示性的例子，说明GEMMs作为研究人类疾病（如癌症）工具的局限性。