Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

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

doi:10.18632/oncotarget.18117

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.

Highlights

Glioblastoma (GBM) is the most common primary brain malignancy
To determine the spatial profile of Notch pathway activation in GBM, we stained 9 formalin-fixed paraffinembedded (FFPE) human GBM biospecimens for Notch1 Intracellular Domain (NICD1) (Supplementary Table 1)
These findings suggest that hypoxia permits tumor growth driven by CD133hi GBM stem cells (GSCs), which are transcriptionally primed for anaerobic glycolysis

Summary

Introduction

Glioblastoma (GBM) is the most common primary brain malignancy (http://www.cbtrus.org). GBM growth is maintained by a dynamic cellular www.impactjournals.com/oncotarget hierarchy dominated by GBM stem cells (GSCs) [4,5,6,7,8,9,10]. GBM’s microenvironmental heterogeneity is highlighted by areas of microvascular proliferation interspersed with hypoxic regions of pseudopalisading necrosis (PPN) [17]. Both microenvironments harbor GSCs [18,19,20,21,22,23,24,25,26,27].

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Results

Conclusion