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Cell Rep. 2014 Dec 24;9(6):2233-49. doi: 10.1016/j.celrep.2014.11.025. Epub 2014 Dec 11.

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

Author information

1
Department of Pathology, UT Southwestern, Dallas, TX 75390, USA.
2
Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA.
3
Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
4
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
5
Department of Cell Biology, UT Southwestern, Dallas, TX 75390, USA.
6
Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA; Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA.
7
Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA.
8
Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA. Electronic address: agnes.witkiewicz@utsouthwestern.edu.

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.

PMID:
25497091
DOI:
10.1016/j.celrep.2014.11.025
[Indexed for MEDLINE]
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