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

Emelyn H. Shroff; Livia S. Eberlin; Vanessa M. Dang; Arvin M. Gouw; Meital Gabay; Stacey J. Adam; David I. Bellovin; Phuoc T. Trand; William M. Philbrick; Adolfo Garcia-Ocana; Stephanie C. Casey; Yulin Li; Chi V. Dang; Richard N. Zare; Dean W. Felsher

doi:10.1073/pnas.1507228112

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

Emelyn H. Shroff, Livia S. Eberlin, Vanessa M. Dang, Arvin M. Gouw, Meital Gabay, Stacey J. Adam, David I. Bellovin, Phuoc T. Trand, William M. Philbrick, Adolfo Garcia-Ocana, Stephanie C. Casey, Yulin Li, Chi V. Dang, Richard N. Zare, Dean W. Felsher

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114 Scopus citations

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.

Original language	English (US)
Pages (from-to)	6539-6544
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	21
DOIs	https://doi.org/10.1073/pnas.1507228112
State	Published - May 26 2015
Externally published	Yes

Keywords

Desorption electrospray ionization mass spectrometry imaging
Glutamine metabolism
MYC oncogene
Renal cell carcinoma

ASJC Scopus subject areas

General

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10.1073/pnas.1507228112

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Shroff, E. H., Eberlin, L. S., Dang, V. M., Gouw, A. M., Gabay, M., Adam, S. J., Bellovin, D. I., Trand, P. T., Philbrick, W. M., Garcia-Ocana, A., Casey, S. C., Li, Y., Dang, C. V., Zare, R. N., & Felsher, D. W. (2015). MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proceedings of the National Academy of Sciences of the United States of America, 112(21), 6539-6544. https://doi.org/10.1073/pnas.1507228112

Shroff, EH, Eberlin, LS, Dang, VM, Gouw, AM, Gabay, M, Adam, SJ, Bellovin, DI, Trand, PT, Philbrick, WM, Garcia-Ocana, A, Casey, SC, Li, Y, Dang, CV, Zare, RN & Felsher, DW 2015, 'MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 21, pp. 6539-6544. https://doi.org/10.1073/pnas.1507228112

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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.",

keywords = "Desorption electrospray ionization mass spectrometry imaging, Glutamine metabolism, MYC oncogene, Renal cell carcinoma",

author = "Shroff, {Emelyn H.} and Eberlin, {Livia S.} and Dang, {Vanessa M.} and Gouw, {Arvin M.} and Meital Gabay and Adam, {Stacey J.} and Bellovin, {David I.} and Trand, {Phuoc T.} and Philbrick, {William M.} and Adolfo Garcia-Ocana and Casey, {Stephanie C.} and Yulin Li and Dang, {Chi V.} and Zare, {Richard N.} and Felsher, {Dean W.}",

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doi = "10.1073/pnas.1507228112",

language = "English (US)",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

AU - Shroff, Emelyn H.

AU - Eberlin, Livia S.

AU - Dang, Vanessa M.

AU - Gouw, Arvin M.

AU - Gabay, Meital

AU - Adam, Stacey J.

AU - Bellovin, David I.

AU - Trand, Phuoc T.

AU - Philbrick, William M.

AU - Garcia-Ocana, Adolfo

AU - Casey, Stephanie C.

AU - Li, Yulin

AU - Dang, Chi V.

AU - Zare, Richard N.

AU - Felsher, Dean W.

PY - 2015/5/26

Y1 - 2015/5/26

N2 - 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.

AB - 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.

KW - Desorption electrospray ionization mass spectrometry imaging

KW - Glutamine metabolism

KW - MYC oncogene

KW - Renal cell carcinoma

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

Abstract

Keywords

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