title: MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies.
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.
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX 75390, USA.
authors.forename: GuemHee
authors.initials: G
authors.lastname: Baek
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Yan F
authors.initials: YF
authors.lastname: Tse
authors.affiliation: Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Zeping
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Cox
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Buboltz
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: McCue
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Department of Cell Biology, UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA; Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA. Electronic address: agnes.witkiewicz@utsouthwestern.edu.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D006019:Glycolysis; D006801:Humans; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; C406962:SLC16A4 protein, human