Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells
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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
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
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.
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