MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies

Guem Hee Baek, Yan F. Tse, Zeping Hu, Derek Cox, Noah Buboltz, Peter McCue, Charles J. Yeo, Michael A. White, Ralph J. DeBerardinis, Erik S. Knudsen, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

KRAS mutation, which occurs in ~95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate themetabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions.

Original languageEnglish (US)
Pages (from-to)2233-2249
Number of pages17
JournalCell Reports
Volume9
Issue number6
DOIs
StatePublished - Dec 24 2014

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Pancreatic Neoplasms
Metabolism
Tumors
Adenocarcinoma
Cell death
Monocarboxylic Acid Transporters
Neoplasms
Cell Death
Scavenging
Metabolites
Heterografts
Gene expression
Reactive Oxygen Species
Oxidative Phosphorylation
Autophagy
Growth
Fluxes
Gene Expression
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies. / Baek, Guem Hee; Tse, Yan F.; Hu, Zeping; Cox, Derek; Buboltz, Noah; McCue, Peter; Yeo, Charles J.; White, Michael A.; DeBerardinis, Ralph J.; Knudsen, Erik S.; Witkiewicz, Agnieszka K.

In: Cell Reports, Vol. 9, No. 6, 24.12.2014, p. 2233-2249.

Research output: Contribution to journalArticle

Baek, Guem Hee ; Tse, Yan F. ; Hu, Zeping ; Cox, Derek ; Buboltz, Noah ; McCue, Peter ; Yeo, Charles J. ; White, Michael A. ; DeBerardinis, Ralph J. ; Knudsen, Erik S. ; Witkiewicz, Agnieszka K. / MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies. In: Cell Reports. 2014 ; Vol. 9, No. 6. pp. 2233-2249.
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AU - McCue, Peter

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AU - White, Michael A.

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AB - KRAS mutation, which occurs in ~95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate themetabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions.

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