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 & 3 others Pankaj K. Singh, David B. Shackelford, Jung Whan Kim

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Article number15503
JournalNature Communications
Volume8
DOIs
StatePublished - May 26 2017

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phenotype
vulnerability
Non-Small Cell Lung Carcinoma
lungs
Squamous Cell Carcinoma
cancer
Phenotype
Lung
Cells
Glycolysis
Glucose
Facilitative Glucose Transport Proteins
glycolysis
glucose
Neoplasms
Heterografts
Atlases
Tumors
Genes
Epithelial Cells

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Goodwin, J., Neugent, M. L., Lee, S. Y., Choe, J. H., Choi, H., Enkins, D. M. R. J., ... Kim, J. W. (2017). The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nature Communications, 8, [15503]. https://doi.org/10.1038/ncomms15503

The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. / Goodwin, Justin; Neugent, Michael L.; Lee, Shin Yup; Choe, Joshua H.; Choi, Hyunsung; Enkins, Dana M.R.J.; Ruthenborg, Robin J.; Robinson, Maddox W.; Jeong, Ji Yun; Wake, Masaki; Abe, Hajime; Takeda, Norihiko; Endo, Hiroko; Inoue, Masahiro; Xuan, Zhenyu; Yoo, Hyuntae; Chen, Min; Ahn, Jung Mo; Minna, John D.; Helke, Kristi L.; Singh, Pankaj K.; Shackelford, David B.; Kim, Jung Whan.

In: Nature Communications, Vol. 8, 15503, 26.05.2017.

Research output: Contribution to journalArticle

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
Goodwin, Justin ; Neugent, Michael L. ; Lee, Shin Yup ; Choe, Joshua H. ; Choi, Hyunsung ; Enkins, Dana M.R.J. ; Ruthenborg, Robin J. ; Robinson, Maddox W. ; Jeong, Ji Yun ; Wake, Masaki ; Abe, Hajime ; Takeda, Norihiko ; Endo, Hiroko ; Inoue, Masahiro ; Xuan, Zhenyu ; Yoo, Hyuntae ; Chen, Min ; Ahn, Jung Mo ; Minna, John D. ; Helke, Kristi L. ; Singh, Pankaj K. ; Shackelford, David B. ; Kim, Jung Whan. / The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. In: Nature Communications. 2017 ; Vol. 8.
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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.",
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