title: MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.
abstract: The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Emelyn H
authors.initials: EH
authors.lastname: Shroff
authors.affiliation: Department of Chemistry, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Livia S
authors.initials: LS
authors.lastname: Eberlin
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Dang
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Arvin M
authors.initials: AM
authors.lastname: Gouw
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Meital
authors.initials: M
authors.lastname: Gabay
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Adam
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: David I
authors.initials: DI
authors.lastname: Bellovin
authors.affiliation: Departments of Radiation Oncology and Molecular Radiation Sciences, and Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.affiliation: Center on Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: William M
authors.initials: WM
authors.lastname: Philbrick
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocana
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Casey
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: Department of Chemistry, Stanford University School of Medicine, Stanford, CA 94305; zare@stanford.edu dfelsher@stanford.edu.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Zare
authors.affiliation: Division of Medical Oncology, Departments of Medicine and Pathology, and zare@stanford.edu dfelsher@stanford.edu.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016259:Genes, myc; D011905:Genes, ras; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005973:Glutamine; D005972:Glutaminase
keywords: MYC oncogene; desorption electrospray ionization mass spectrometry imaging; glutamine metabolism; renal cell carcinoma