The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition.
The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition.
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DOI：
10.1038/ncomms15503
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发表时间：
2017-05-26
影响因子：
16.6
通讯作者：
Kim JW
中科院分区：
文献类型：
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作者：
Goodwin J;Neugent ML;Lee SY;Choe JH;Choi H;Jenkins DMR;Ruthenborg RJ;Robinson MW;Jeong JY;Wake M;Abe H;Takeda N;Endo H;Inoue M;Xuan Z;Yoo H;Chen M;Ahn JM;Minna JD;Helke KL;Singh PK;Shackelford DB;Kim JW
腺癌（ADC）和鳞状细胞癌（SqCC）是非小细胞肺癌（NSCLC）的两种主要亚型，在组织学、分子生物学和临床表现上各不相同。然而，特定于个体NSCLC亚型的代谢特征仍然未知。在这里，我们对人类NSCLC肿瘤样本，患者来源的异种移植物，NSCLC小鼠模型，NSCLC细胞系和癌症基因组图谱（TCGA）进行了综合分析，并揭示了GLUT 1葡萄糖转运蛋白在肺SqCC中的表达显著升高，这增加了葡萄糖摄取和糖酵解通量。我们表明，对糖酵解的严重依赖使肺SqCC容易受到糖酵解抑制，而肺ADC表现出显着的葡萄糖依赖性。临床上，肺SqCC中GLUT 1介导的糖酵解升高与18F-FDG高摄取和预后不良密切相关。NSCLC亚型的这种先前未描述的代谢异质性暗示了为肺SqCC开发诊断、预后和靶向治疗策略的巨大潜力，肺SqCC是一种现有治疗方案在临床上不足的癌症。腺癌和鳞状细胞癌是非小细胞肺癌的不同亚型。在这里，作者表明，糖酵解通量增加，通过增加葡萄糖转运蛋白Glut 1的表达，是鳞状细胞癌的核心代谢特征，使其对糖酵解抑制敏感。
Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient. Adenocarcinoma and squamous cell carcinoma are distinct subtypes of non-small cell lung cancer. Here, the authors show that increased glycolytic flux, via increased glucose transporter Glut1 expression, is a core metabolic feature of squamous cell carcinoma that renders it sensitive to glycolysis inhibition.