MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 21; pp. 6539 - 6544
• Main Authors: Shroff, Emelyn H., Eberlin, Livia S., Dang, Vanessa M., Gouw, Arvin M., Gabay, Meital, Adam, Stacey J., Bellovin, David I., Tran, Phuoc T., Philbrick, William M., Garcia-Ocana, Adolfo, Casey, Stephanie C., Li, Yulin, Dang, Chi V., Zare, Richard N., Felsher, Dean W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.05.2015; National Acad Sciences
• Subjects: animal models; Animals; Biological Sciences; carcinoma; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Desorption; Disease Models, Animal; Disease Progression; Enzyme Inhibitors - pharmacology; Gene expression; gene expression regulation; gene overexpression; Genes, myc; Genes, ras; genetic techniques and protocols; glutaminase; Glutaminase - antagonists & inhibitors; Glutaminase - metabolism; glutamine; Glutamine - metabolism; Humans; image analysis; immunohistochemistry; Ionization; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; kidneys; Lipid Metabolism; Lipids; Metabolism; Metabolites; Mice; Mice, SCID; Mice, Transgenic; neoplasm cells; oncogenes; Physical Sciences; proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Rodents; Spectrometry, Mass, Electrospray Ionization; Sulfides - pharmacology; Thiadiazoles - pharmacology; transgenic animals; Tumors; Up-Regulation; glutamine metabolism; renal cell carcinoma; MYC oncogene; desorption electrospray ionization mass spectrometry imaging
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507228112

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. Significance The absence of appropriate transgenic animal models of renal cell carcinomas (RCCs) has made it difficult to identify and test new therapies for this disease. We developed a new transgenic mouse model of a highly aggressive form of RCC in which tumor growth and regression is conditionally regulated by the MYC oncogene. Using desorption electrospray ionization–mass-spectrometric imaging, we found that certain glycerophosphoglycerols and metabolites of the glutaminolytic pathway were higher in abundance in RCC than in normal kidney tissue. Up-regulation of glutaminolytic genes and proteins was identified by genetic analysis and immunohistochemistry, therefore suggesting that RCC tumors are glutamine addicted. Pharmacological inhibition of glutaminase slowed tumor progression in vivo, which may represent a novel therapeutic route for RCC.