The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition.

Abstract

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.

• Authors: Justin Goodwin, Michael L Neugent, Shin Yup Lee, Joshua H Choe, Hyunsung Choi, Dana M R Jenkins, Robin J Ruthenborg, Maddox W Robinson, Ji Yun Jeong, Masaki Wake, Hajime Abe, Norihiko Takeda, Hiroko Endo, Masahiro Inoue, Zhenyu Xuan, Hyuntae Yoo, Min Chen, Jung-Mo Ahn, John D Minna, Kristi L Helke, Pankaj K Singh, David B Shackelford, Jung-Whan Kim
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 15503 (05 26 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28548087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 1
• Hydroxybenzoates
• SLC2A1 protein, human
• WZB117
• Fluorodeoxyglucose F18
• Deoxyglucose
• Glucose

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Adenocarcinoma of Lung
• Adult
• Aged
• Aged, 80 and over
• Animals
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging, genetics, metabolism, mortality)
• Carcinoma, Squamous Cell (diagnostic imaging, genetics, metabolism, mortality)
• Cell Line, Tumor
• Cohort Studies
• Deoxyglucose (pharmacology)
• Female
• Fluorodeoxyglucose F18 (administration & dosage)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glucose (metabolism)
• Glucose Transporter Type 1 (antagonists & inhibitors, metabolism)
• Glycolysis (drug effects, genetics)
• Humans
• Hydroxybenzoates (pharmacology)
• Lung (diagnostic imaging, pathology)
• Lung Neoplasms (diagnostic imaging, genetics, metabolism, mortality, pathology)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Phenotype
• Positron-Emission Tomography
• Prognosis
• Survival Analysis
• Up-Regulation
• Xenograft Model Antitumor Assays