Cargando…

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch...

Descripción completa

Detalles Bibliográficos
Autores principales: Bayin, N. Sumru, Frenster, Joshua D., Sen, Rajeev, Si, Sheng, Modrek, Aram S., Galifianakis, Nataliya, Dolgalev, Igor, Ortenzi, Valerio, Illa-Bochaca, Irineu, Khahera, Anadjeet, Serrano, Jonathan, Chiriboga, Luis, Zagzag, David, Golfinos, John G., Doyle, Werner, Tsirigos, Aristotelis, Heguy, Adriana, Chesler, Mitch, Barcellos-Hoff, Mary Helen, Snuderl, Matija, Placantonakis, Dimitris G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630302/
https://www.ncbi.nlm.nih.gov/pubmed/29029402
http://dx.doi.org/10.18632/oncotarget.18117
_version_ 1783269194334208000
author Bayin, N. Sumru
Frenster, Joshua D.
Sen, Rajeev
Si, Sheng
Modrek, Aram S.
Galifianakis, Nataliya
Dolgalev, Igor
Ortenzi, Valerio
Illa-Bochaca, Irineu
Khahera, Anadjeet
Serrano, Jonathan
Chiriboga, Luis
Zagzag, David
Golfinos, John G.
Doyle, Werner
Tsirigos, Aristotelis
Heguy, Adriana
Chesler, Mitch
Barcellos-Hoff, Mary Helen
Snuderl, Matija
Placantonakis, Dimitris G.
author_facet Bayin, N. Sumru
Frenster, Joshua D.
Sen, Rajeev
Si, Sheng
Modrek, Aram S.
Galifianakis, Nataliya
Dolgalev, Igor
Ortenzi, Valerio
Illa-Bochaca, Irineu
Khahera, Anadjeet
Serrano, Jonathan
Chiriboga, Luis
Zagzag, David
Golfinos, John G.
Doyle, Werner
Tsirigos, Aristotelis
Heguy, Adriana
Chesler, Mitch
Barcellos-Hoff, Mary Helen
Snuderl, Matija
Placantonakis, Dimitris G.
author_sort Bayin, N. Sumru
collection PubMed
description Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.
format Online
Article
Text
id pubmed-5630302
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-56303022017-10-12 Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells Bayin, N. Sumru Frenster, Joshua D. Sen, Rajeev Si, Sheng Modrek, Aram S. Galifianakis, Nataliya Dolgalev, Igor Ortenzi, Valerio Illa-Bochaca, Irineu Khahera, Anadjeet Serrano, Jonathan Chiriboga, Luis Zagzag, David Golfinos, John G. Doyle, Werner Tsirigos, Aristotelis Heguy, Adriana Chesler, Mitch Barcellos-Hoff, Mary Helen Snuderl, Matija Placantonakis, Dimitris G. Oncotarget Research Paper Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments. Impact Journals LLC 2017-05-23 /pmc/articles/PMC5630302/ /pubmed/29029402 http://dx.doi.org/10.18632/oncotarget.18117 Text en Copyright: © 2017 Bayin et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Bayin, N. Sumru
Frenster, Joshua D.
Sen, Rajeev
Si, Sheng
Modrek, Aram S.
Galifianakis, Nataliya
Dolgalev, Igor
Ortenzi, Valerio
Illa-Bochaca, Irineu
Khahera, Anadjeet
Serrano, Jonathan
Chiriboga, Luis
Zagzag, David
Golfinos, John G.
Doyle, Werner
Tsirigos, Aristotelis
Heguy, Adriana
Chesler, Mitch
Barcellos-Hoff, Mary Helen
Snuderl, Matija
Placantonakis, Dimitris G.
Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title_full Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title_fullStr Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title_full_unstemmed Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title_short Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
title_sort notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630302/
https://www.ncbi.nlm.nih.gov/pubmed/29029402
http://dx.doi.org/10.18632/oncotarget.18117
work_keys_str_mv AT bayinnsumru notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT frensterjoshuad notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT senrajeev notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT sisheng notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT modrekarams notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT galifianakisnataliya notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT dolgalevigor notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT ortenzivalerio notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT illabochacairineu notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT khaheraanadjeet notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT serranojonathan notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT chiribogaluis notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT zagzagdavid notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT golfinosjohng notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT doylewerner notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT tsirigosaristotelis notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT heguyadriana notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT cheslermitch notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT barcelloshoffmaryhelen notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT snuderlmatija notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells
AT placantonakisdimitrisg notchsignalingregulatesmetabolicheterogeneityinglioblastomastemcells