MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies.
Publication/Presentation Date
12-24-2014
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.
Volume
9
Issue
6
First Page
2233
Last Page
2249
ISSN
2211-1247
Published In/Presented At
Baek, G., Tse, Y. F., Hu, Z., Cox, D., Buboltz, N., McCue, P., Yeo, C. J., White, M. A., DeBerardinis, R. J., Knudsen, E. S., & Witkiewicz, A. K. (2014). MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell reports, 9(6), 2233–2249. https://doi.org/10.1016/j.celrep.2014.11.025
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
25497091
Department(s)
Administration and Leadership
Document Type
Article