Journal article
MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies
Cell reports (Cambridge), v 9(6), pp 2233-2249
24 Dec 2014
PMID: 25497091
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 the metabolic 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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Details
- Title
- MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies
- Creators
- GuemHee Baek - Department of Pathology, UT Southwestern, Dallas, TX 75390, USAYan F Tse - Southwestern Medical CenterZeping Hu - The University of Texas Southwestern Medical CenterDerek Cox - Southwestern Medical CenterNoah Buboltz - Thomas Jefferson UniversityPeter McCue - Thomas Jefferson UniversityCharles J Yeo - Thomas Jefferson UniversityMichael A White - Southwestern Medical CenterRalph J DeBerardinis - The University of Texas Southwestern Medical CenterErik S Knudsen - Southwestern Medical CenterAgnieszka K Witkiewicz - Southwestern Medical Center
- Publication Details
- Cell reports (Cambridge), v 9(6), pp 2233-2249
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000346852400022
- Scopus ID
- 2-s2.0-84919863195
- Other Identifier
- 991021448036804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology