Logo image
Back
MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies
Journal article   Open access   Peer reviewed

MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies

GuemHee Baek, Yan F Tse, Zeping Hu, Derek Cox, Noah Buboltz, Peter McCue, Charles J Yeo, Michael A White, Ralph J DeBerardinis, Erik S Knudsen, …
Cell reports (Cambridge), v 9(6), pp 2233-2249
24 Dec 2014
DOI: https://doi.org/10.1016/j.celrep.2014.11.025
PMID: 25497091
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.celrep.2014.11.025View
Published, Version of Record (VoR) Open

Abstract

Animals Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Death Cell Line, Tumor Glycolysis Humans Mice Monocarboxylic Acid Transporters - genetics Monocarboxylic Acid Transporters - metabolism Muscle Proteins - genetics Muscle Proteins - metabolism Oxidative Phosphorylation Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Prognosis Reactive Oxygen Species - metabolism
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.

Metrics

14 Record Views
190 citations in Web of Science
179 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
Web of Science research areas
Cell Biology
Logo image