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

Justin Goodwin; Michael L. Neugent; Shin Yup Lee; Joshua H. Choe; Hyunsung Choi; Dana M.R.J. Enkins; 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

doi:10.1038/ncomms15503

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

Justin Goodwin, Michael L. Neugent, Shin Yup Lee, Joshua H. Choe, Hyunsung Choi, Dana M.R.J. Enkins, 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. HelkePankaj K. Singh, David B. Shackelford, Jung Whan Kim

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115 Scopus citations

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 18 F-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.

Original language	English (US)
Article number	15503
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15503
State	Published - May 26 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Goodwin, J., Neugent, M. L., Lee, S. Y., Choe, J. H., Choi, H., Enkins, D. M. R. J., Ruthenborg, R. J., Robinson, M. W., Jeong, J. Y., Wake, M., Abe, H., Takeda, N., Endo, H., Inoue, M., Xuan, Z., Yoo, H., Chen, M., Ahn, J. M., Minna, J. D., ... Kim, J. W. (2017). The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nature communications, 8, Article 15503. https://doi.org/10.1038/ncomms15503

Goodwin, J, Neugent, ML, Lee, SY, Choe, JH, Choi, H, Enkins, DMRJ, 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 2017, 'The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition', Nature communications, vol. 8, 15503. https://doi.org/10.1038/ncomms15503

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title = "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 18 F-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.",

author = "Justin Goodwin and Neugent, {Michael L.} and Lee, {Shin Yup} and Choe, {Joshua H.} and Hyunsung Choi and Enkins, {Dana M.R.J.} and Ruthenborg, {Robin J.} and Robinson, {Maddox W.} and Jeong, {Ji Yun} and Masaki Wake and Hajime Abe and Norihiko Takeda and Hiroko Endo and Masahiro Inoue and Zhenyu Xuan and Hyuntae Yoo and Min Chen and Ahn, {Jung Mo} and Minna, {John D.} and Helke, {Kristi L.} and Singh, {Pankaj K.} and Shackelford, {David B.} and Kim, {Jung Whan}",

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AU - Goodwin, Justin

AU - Neugent, Michael L.

AU - Lee, Shin Yup

AU - Choe, Joshua H.

AU - Choi, Hyunsung

AU - Enkins, Dana M.R.J.

AU - Ruthenborg, Robin J.

AU - Robinson, Maddox W.

AU - Jeong, Ji Yun

AU - Wake, Masaki

AU - Abe, Hajime

AU - Takeda, Norihiko

AU - Endo, Hiroko

AU - Inoue, Masahiro

AU - Xuan, Zhenyu

AU - Yoo, Hyuntae

AU - Chen, Min

AU - Ahn, Jung Mo

AU - Minna, John D.

AU - Helke, Kristi L.

AU - Singh, Pankaj K.

AU - Shackelford, David B.

AU - Kim, Jung Whan

PY - 2017/5/26

Y1 - 2017/5/26

N2 - 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 18 F-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.

AB - 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 18 F-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.

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

Abstract

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