The Distinct Metabolic Phenotype of Lung Squamous Cell Carcinoma Defines Selective Vulnerability to Glycolytic Inhibition


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 F-18-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.


Includes supplementary material


Messenger RNA, Glucose, Lungs—Cancer, Squamous cell carcinoma, Glucose Transporter Type 1, Adenocarcinoma, Tumors, Cancer—Treatment, Carcinoma, Non-Small-Cell Lung

"This work was supported by the UT Dallas start-up fund and American Lung Association LCD-400239 (J.-w.K.), NIH R01 CA163649 and SPORE 2P50 CA127207 (P.K.S.), NIH K25 AR063761 (M.C.), Project for Development of Innovative Research on Cancer Therapeutics, Japan Agency for Medical Research and Development, JSPS Kakenhi JP26111005 and Takeda Science Foundation (M.I.), JP25461937 (H.E.), Grant-in-Aid for Scientific Research on Promotion of Science, 16K09493, on Innovative Areas, 26111003, JST PRESTO, the Banyu Life Science Foundation International and Takeda Science Foundation (N.T.), Welch Foundation, AT-1595 (J.-M.A.), NIH, NCI P50CA70907 (SPORE), Cancer Prevention and Research Institute of Texas (CPRIT) RP110708 (J.D.M.)."


CC BY 4.0 (Attribution), ©2017 The Authors