Manning, Brendan

Ricoult, Stéphane

Yecies, Jessica

Cancer & Metabolism

Stéphane Ricoult

Jessica Yecies

Brendan Manning

Springer - Publisher Connector

POSTER PRESENTATION Open Access
Oncogenic signaling upstream of mTORC1 drives
lipogenesis and proliferation through SREBP
Stéphane Ricoult1*, Jessica Yecies2, Brendan Manning1
From Metabolism, Diet and Disease 2014: Cancer and metabolism
Washington DC, USA. 28-30 May 2014
Background
The mechanistic target of rapamycin (mTOR) is a central
regulator of cell growth and proliferation, and its aberrant
activation is frequent in cancer [1]. We have previously
shown that sterol regulatory element binding protein
(SREBP) is a major transcriptional effector of mTOR
complex 1 (mTORC1) signaling [2]. SREBP is a transcrip-
tion factor that stimulates the expression of genes involved
in the de novo synthesis of lipids [3]. Since mTORC1
is commonly activated in cancer through upstream
oncogenic signaling pathways and enhanced lipogenesis is
a metabolic hallmark of tumor cells, we hypothesize that
the mTORC1-SREBP pathway is important for tumor
metabolism and growth.
Materials and methods
We used a panel of breast cancer cell lines with various
mutations resulting in constitutive mTORC1 activation,
as well as MCF10a cells transformed with oncogenic
KRAS or PIK3CA to explore the role of SREBP in
mTORC1-driven cancers. We used chemical inhibitors
and siRNAs to assess the dependence of our breast
cancer systems on the mTORC1-SREBP pathway for de
novo lipogenesis, proliferation, growth, and cell survival.
Results
Using both the panel of breast cancer cell lines and the
isogenic MCF10a cell lines, we have revealed an essential
role for SREBP in driving lipogenesis and proliferation in
tumor cells. Our results indicate that SREBP and its
lipogenic targets are activated in cell lines with oncogene-
induced mTORC1 signaling, and this activation was
ablated by mTOR inhibitors. mTORC1 signaling promotes
de novo lipogenesis in an SREBP-dependent manner in
cancer cells. In addition, we found that the mTORC1-
stimulated activation of SREBP2 promotes cell growth,
proliferation, and survival of breast cancer cells. We are in
the process of identifying the essential functions of
SREBP2 in breast cancer and assessing the dependence of
breast cancer cells on SREBP2 in vivo. These findings
emphasize the therapeutic potential of targeting lipid
metabolism in cancers, particularly those with activated
mTORC1 signaling.
Authors’ details
1Genetics and Complex Diseases, Harvard School of Public Health, Boston,
MA, USA. 2Genentech, South San Francisco, CA, USA.
Published: 28 May 2014
References
1. Menon S, Manning BD: Common corruption of the mTOR signaling
network in human tumors. Oncogene 2008, 27:S43-S51.
2. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL,
Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG,
MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD: Activation of a
metabolic gene regulatory network downstream of mTOR complex 1.
Mol Cell 2010, 39:171-183.
3. Ricoult SJH, Manning BD: The multifaceted role of mTORC1 in the control
of lipid metabolism. EMBO Rep 2013, 14:242-251.
doi:10.1186/2049-3002-2-S1-P62
Cite this article as: Ricoult et al.: Oncogenic signaling upstream of
mTORC1 drives lipogenesis and proliferation through SREBP. Cancer &
Metabolism 2014 2(Suppl 1):P62.
1Genetics and Complex Diseases, Harvard School of Public Health, Boston,
MA, USA
Full list of author information is available at the end of the article
Ricoult et al. Cancer & Metabolism 2014, 2(Suppl 1):P62
http://www.cancerandmetabolism.com/content/2/S1/P62 Cancer & 
Metabolism
© 2014 Ricoult et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


Oncogenic signaling upstream of mTORC1 drives lipogenesis and proliferation through SREBP

Harvard University - DASH 

 Oncogenic signaling upstream of mTORC1 drives lipogenesisand proliferation through SREBP  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Ricoult, Stéphane, Jessica Yecies, and Brendan Manning. 2014.“Oncogenic signaling upstream of mTORC1 drives lipogenesisand proliferation through SREBP.” Cancer & Metabolism 2(Suppl 1): P62. doi:10.1186/2049-3002-2-S1-P62.http://dx.doi.org/10.1186/2049-3002-2-S1-P62.Published Version doi:10.1186/2049-3002-2-S1-P62Accessed February 16, 2015 3:40:38 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12717440Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAPOSTER PRESENTATION Open AccessOncogenic signaling upstream of mTORC1 driveslipogenesis and proliferation through SREBPStéphane Ricoult1*, Jessica Yecies2, Brendan Manning1From Metabolism, Diet and Disease 2014: Cancer and metabolismWashington DC, USA. 28-30 May 2014BackgroundThe mechanistic target of rapamycin (mTOR) is a centralregulator of cell growth and proliferation, and its aberrantactivation is frequent in cancer [1]. We have previouslyshown that sterol regulatory element binding protein(SREBP) is a major transcriptional effector of mTORcomplex 1 (mTORC1) signaling [2]. SREBP is a transcrip-tion factor that stimulates the expression of genes involvedin the de novo synthesis of lipids [3]. Since mTORC1is commonly activated in cancer through upstreamoncogenic signaling pathways and enhanced lipogenesis isa metabolic hallmark of tumor cells, we hypothesize thatthe mTORC1-SREBP pathway is important for tumormetabolism and growth.Materials and methodsWe used a panel of breast cancer cell lines with variousmutations resulting in constitutive mTORC1 activation,as well as MCF10a cells transformed with oncogenicKRAS or PIK3CA to explore the role of SREBP inmTORC1-driven cancers. We used chemical inhibitorsand siRNAs to assess the dependence of our breastcancer systems on the mTORC1-SREBP pathway for denovo lipogenesis, proliferation, growth, and cell survival.ResultsUsing both the panel of breast cancer cell lines and theisogenic MCF10a cell lines, we have revealed an essentialrole for SREBP in driving lipogenesis and proliferation intumor cells. Our results indicate that SREBP and itslipogenic targets are activated in cell lines with oncogene-induced mTORC1 signaling, and this activation wasablated by mTOR inhibitors. mTORC1 signaling promotesde novo lipogenesis in an SREBP-dependent manner incancer cells. In addition, we found that the mTORC1-stimulated activation of SREBP2 promotes cell growth,proliferation, and survival of breast cancer cells. We are inthe process of identifying the essential functions ofSREBP2 in breast cancer and assessing the dependence ofbreast cancer cells on SREBP2 in vivo.T h e s ef i n d i n g semphasize the therapeutic potential of targeting lipidmetabolism in cancers, particularly those with activatedmTORC1 signaling.Authors’ details1Genetics and Complex Diseases, Harvard School of Public Health, Boston,MA, USA.2Genentech, South San Francisco, CA, USA.Published: 28 May 2014References1. Menon S, Manning BD: Common corruption of the mTOR signalingnetwork in human tumors. Oncogene 2008, 27:S43-S51.2. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL,Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG,MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD: Activation of ametabolic gene regulatory network downstream of mTOR complex 1.Mol Cell 2010, 39:171-183.3. Ricoult SJH, Manning BD: The multifaceted role of mTORC1 in the controlof lipid metabolism. EMBO Rep 2013, 14:242-251.doi:10.1186/2049-3002-2-S1-P62Cite this article as: Ricoult et al.: Oncogenic signaling upstream ofmTORC1 drives lipogenesis and proliferation through SREBP. Cancer &Metabolism 2014 2(Suppl 1):P62.1Genetics and Complex Diseases, Harvard School of Public Health, Boston,MA, USAFull list of author information is available at the end of the articleRicoult et al. Cancer & Metabolism 2014, 2(Suppl 1):P62http://www.cancerandmetabolism.com/content/2/S1/P62 Cancer & Metabolism© 2014 Ricoult et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Oncogenic signaling upstream of mTORC1 drives lipogenesis and proliferation through SREBP

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