The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type

Mariia O. Yuneva; Teresa W.M. Fan; Thaddeus D. Allen; Richard M. Higashi; Dana V. Ferraris; Takashi Tsukamoto; José M. Matés; Francisco J. Alonso; Chunmei Wang; Youngho Seo; Xin Chen; J. Michael Bishop

doi:10.1016/j.cmet.2011.12.015

The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type

Mariia O. Yuneva, Teresa W.M. Fan, Thaddeus D. Allen, Richard M. Higashi, Dana V. Ferraris, Takashi Tsukamoto, José M. Matés, Francisco J. Alonso, Chunmei Wang, Youngho Seo, Xin Chen, J. Michael Bishop

Research output: Contribution to journal › Article › peer-review

534 Scopus citations

Abstract

The altered metabolism of tumors has been considered a target for anticancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that overexpress MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.

Original language	English
Pages (from-to)	157-170
Number of pages	14
Journal	Cell Metabolism
Volume	15
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2011.12.015
State	Published - Feb 8 2012

Bibliographical note

Funding Information:
We thank Dr. A. Lane, Dr. S. Arumugam, J. Tan, and R. Burra (University of Louisville, Louisville, KY) for help with metabolic profiling analysis and Dr. A. Lane for valuable comments on the manuscript; Drs. A. Goga and A. Balakrishnan (University of California, San Francisco, San Francisco, CA) for useful discussion of preliminary results; L. Urisman (University of California, San Francisco, San Francisco, CA) for assistance with animal husbandry; and members of the Bishop Laboratory for valuable discussions and comments. NMR analyses were supported in part by National Institutes of Health (NIH) Grant P20RR018733 from the National Center for Research Resources and National Science Foundation (NSF) EPSCoR grant EPS-0447479. Metabolite profiling analysis was supported by NSF EPSCoR grant EPS-0447479, National Cancer Institute (NCI) grants 1R01CA118434-01A2 and 3R01 CA118434-02S1; and University of Louisville CTSPGP award (T.W.M.F.). The work was also supported by UCSF/G.W. Hooper Research Foundation Endowment Funds and by NCI Grant R35 CA44338 (J.M.B.); by UCSF Hellen Diller Family Comprehensive Cancer Center Pilot Grant and the UCSF Department of Radiology and Biomedical Imaging Seed Grant 10-09 (X.C. and Y.S.); by the Johns Hopkins Brain Science Institute through the NeuroTranslational Program (T.T. and D.V.F.); by NIH Grant R21NS074151 (to T.T.); and by Ministerio de Ciencia y Tecnología SAF2010-17573 and Junta de Andalucía, Proyectos de Investigación de Excelencia, Convocatoria 2010, CVI-6656, Spain (J.M.M. and F.J.A.).

Funding

We thank Dr. A. Lane, Dr. S. Arumugam, J. Tan, and R. Burra (University of Louisville, Louisville, KY) for help with metabolic profiling analysis and Dr. A. Lane for valuable comments on the manuscript; Drs. A. Goga and A. Balakrishnan (University of California, San Francisco, San Francisco, CA) for useful discussion of preliminary results; L. Urisman (University of California, San Francisco, San Francisco, CA) for assistance with animal husbandry; and members of the Bishop Laboratory for valuable discussions and comments. NMR analyses were supported in part by National Institutes of Health (NIH) Grant P20RR018733 from the National Center for Research Resources and National Science Foundation (NSF) EPSCoR grant EPS-0447479. Metabolite profiling analysis was supported by NSF EPSCoR grant EPS-0447479, National Cancer Institute (NCI) grants 1R01CA118434-01A2 and 3R01 CA118434-02S1; and University of Louisville CTSPGP award (T.W.M.F.). The work was also supported by UCSF/G.W. Hooper Research Foundation Endowment Funds and by NCI Grant R35 CA44338 (J.M.B.); by UCSF Hellen Diller Family Comprehensive Cancer Center Pilot Grant and the UCSF Department of Radiology and Biomedical Imaging Seed Grant 10-09 (X.C. and Y.S.); by the Johns Hopkins Brain Science Institute through the NeuroTranslational Program (T.T. and D.V.F.); by NIH Grant R21NS074151 (to T.T.); and by Ministerio de Ciencia y Tecnología SAF2010-17573 and Junta de Andalucía, Proyectos de Investigación de Excelencia, Convocatoria 2010, CVI-6656, Spain (J.M.M. and F.J.A.).

Funders	Funder number
National Science Foundation (NSF)
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R35CA044338, 1R01CA118434-01A2
National Center for Research Resources	P20RR018733
Office of Experimental Program to Stimulate Competitive Research	EPS-0447479
University of Louisville	R35 CA44338
University of California San Francisco	10-09
Brain Science Institute, Johns Hopkins University	R21NS074151
Kansas NSF EPSCoR
Ministerio de Ciencia, Tecnología e Innovación Productiva	SAF2010-17573
Junta de Andalucía	CVI-6656

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2011.12.015

Cite this

@article{cc4a4fd96949406fb4fcb735d01dbbab,

title = "The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type",

abstract = "The altered metabolism of tumors has been considered a target for anticancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that overexpress MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.",

author = "Yuneva, {Mariia O.} and Fan, {Teresa W.M.} and Allen, {Thaddeus D.} and Higashi, {Richard M.} and Ferraris, {Dana V.} and Takashi Tsukamoto and Mat{\'e}s, {Jos{\'e} M.} and Alonso, {Francisco J.} and Chunmei Wang and Youngho Seo and Xin Chen and Bishop, {J. Michael}",

note = "Funding Information: We thank Dr. A. Lane, Dr. S. Arumugam, J. Tan, and R. Burra (University of Louisville, Louisville, KY) for help with metabolic profiling analysis and Dr. A. Lane for valuable comments on the manuscript; Drs. A. Goga and A. Balakrishnan (University of California, San Francisco, San Francisco, CA) for useful discussion of preliminary results; L. Urisman (University of California, San Francisco, San Francisco, CA) for assistance with animal husbandry; and members of the Bishop Laboratory for valuable discussions and comments. NMR analyses were supported in part by National Institutes of Health (NIH) Grant P20RR018733 from the National Center for Research Resources and National Science Foundation (NSF) EPSCoR grant EPS-0447479. Metabolite profiling analysis was supported by NSF EPSCoR grant EPS-0447479, National Cancer Institute (NCI) grants 1R01CA118434-01A2 and 3R01 CA118434-02S1; and University of Louisville CTSPGP award (T.W.M.F.). The work was also supported by UCSF/G.W. Hooper Research Foundation Endowment Funds and by NCI Grant R35 CA44338 (J.M.B.); by UCSF Hellen Diller Family Comprehensive Cancer Center Pilot Grant and the UCSF Department of Radiology and Biomedical Imaging Seed Grant 10-09 (X.C. and Y.S.); by the Johns Hopkins Brain Science Institute through the NeuroTranslational Program (T.T. and D.V.F.); by NIH Grant R21NS074151 (to T.T.); and by Ministerio de Ciencia y Tecnolog{\'i}a SAF2010-17573 and Junta de Andaluc{\'i}a, Proyectos de Investigaci{\'o}n de Excelencia, Convocatoria 2010, CVI-6656, Spain (J.M.M. and F.J.A.). ",

year = "2012",

month = feb,

day = "8",

doi = "10.1016/j.cmet.2011.12.015",

language = "English",

volume = "15",

pages = "157--170",

number = "2",

}

TY - JOUR

T1 - The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type

AU - Yuneva, Mariia O.

AU - Fan, Teresa W.M.

AU - Allen, Thaddeus D.

AU - Higashi, Richard M.

AU - Ferraris, Dana V.

AU - Tsukamoto, Takashi

AU - Matés, José M.

AU - Alonso, Francisco J.

AU - Wang, Chunmei

AU - Seo, Youngho

AU - Chen, Xin

AU - Bishop, J. Michael

N1 - Funding Information: We thank Dr. A. Lane, Dr. S. Arumugam, J. Tan, and R. Burra (University of Louisville, Louisville, KY) for help with metabolic profiling analysis and Dr. A. Lane for valuable comments on the manuscript; Drs. A. Goga and A. Balakrishnan (University of California, San Francisco, San Francisco, CA) for useful discussion of preliminary results; L. Urisman (University of California, San Francisco, San Francisco, CA) for assistance with animal husbandry; and members of the Bishop Laboratory for valuable discussions and comments. NMR analyses were supported in part by National Institutes of Health (NIH) Grant P20RR018733 from the National Center for Research Resources and National Science Foundation (NSF) EPSCoR grant EPS-0447479. Metabolite profiling analysis was supported by NSF EPSCoR grant EPS-0447479, National Cancer Institute (NCI) grants 1R01CA118434-01A2 and 3R01 CA118434-02S1; and University of Louisville CTSPGP award (T.W.M.F.). The work was also supported by UCSF/G.W. Hooper Research Foundation Endowment Funds and by NCI Grant R35 CA44338 (J.M.B.); by UCSF Hellen Diller Family Comprehensive Cancer Center Pilot Grant and the UCSF Department of Radiology and Biomedical Imaging Seed Grant 10-09 (X.C. and Y.S.); by the Johns Hopkins Brain Science Institute through the NeuroTranslational Program (T.T. and D.V.F.); by NIH Grant R21NS074151 (to T.T.); and by Ministerio de Ciencia y Tecnología SAF2010-17573 and Junta de Andalucía, Proyectos de Investigación de Excelencia, Convocatoria 2010, CVI-6656, Spain (J.M.M. and F.J.A.).

PY - 2012/2/8

Y1 - 2012/2/8

N2 - The altered metabolism of tumors has been considered a target for anticancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that overexpress MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.

AB - The altered metabolism of tumors has been considered a target for anticancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that overexpress MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.

UR - http://www.scopus.com/inward/record.url?scp=84863011452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863011452&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2011.12.015

DO - 10.1016/j.cmet.2011.12.015

M3 - Article

C2 - 22326218

AN - SCOPUS:84863011452

SN - 1550-4131

VL - 15

SP - 157

EP - 170

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this