Oncotarget

Research Papers:

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells

N. Sumru Bayin, Joshua D. Frenster, Rajeev Sen, Sheng Si, Aram S. Modrek, Nataliya Galifianakis, Igor Dolgalev, Valerio Ortenzi, Irineu Illa-Bochaca, Anadjeet Khahera, Jonathan Serrano, Luis Chiriboga, David Zagzag, John G. Golfinos, Werner Doyle, Aristotelis Tsirigos, Adriana Heguy, Mitch Chesler, Mary Helen Barcellos-Hoff, Matija Snuderl, Dimitris G. Placantonakis _

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Abstract

N. Sumru Bayin1,2,11, Joshua D. Frenster1,2, Rajeev Sen1, Sheng Si1,12, Aram S. Modrek1, Nataliya Galifianakis1,3, Igor Dolgalev4, Valerio Ortenzi5, Irineu Illa-Bochaca6, Anadjeet Khahera1, Jonathan Serrano5, Luis Chiriboga5, David Zagzag1,5,8,9, John G. Golfinos1,8,9, Werner Doyle1, Aristotelis Tsirigos5,10, Adriana Heguy4, Mitch Chesler1,3, Mary Helen Barcellos-Hoff7,13, Matija Snuderl5,8,9 and Dimitris G. Placantonakis1,2,3,8,9

1 Department of Neurosurgery, NYU School of Medicine, New York, NY, USA

2 Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY, USA

3 Neuroscience Institute, NYU School of Medicine, New York, NY, USA

4 Genome Technology Center, NYU School of Medicine, New York, NY, USA

5 Department of Pathology, NYU School of Medicine, New York, NY, USA

6 Department of Medicine, NYU School of Medicine, New York, NY, USA

7 Department of Radiation Oncology, NYU School of Medicine, New York, NY, USA

8 Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA

9 Brain Tumor Center, NYU School of Medicine, New York, NY, USA

10 Applied Bioinformatics Laboratories, Office of Science & Research, NYU School of Medicine, New York, NY, USA

11 Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA

12 Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

13 Department of Radiation Oncology, University of California, San Francisco, CA, USA

Correspondence to:

Dimitris G. Placantonakis, email:

Keywords: tumor metabolism, glioblastoma stem cells, Notch signaling, CD133, tumor vasculature

Received: May 07, 2017 Accepted: May 10, 2017 Published: May 23, 2017

Abstract

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.

Author Information

N. Sumru Bayin

Joshua D. Frenster

Rajeev Sen

Sheng Si

Aram S. Modrek

Nataliya Galifianakis

Igor Dolgalev

Valerio Ortenzi

Irineu Illa-Bochaca

Anadjeet Khahera

Jonathan Serrano

Luis Chiriboga

David Zagzag

John G. Golfinos

Werner Doyle

Aristotelis Tsirigos

Adriana Heguy

Mitch Chesler

Mary Helen Barcellos-Hoff

Matija Snuderl

Dimitris G. Placantonakis
Primary Contact  _


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