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Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake

Nature Neuroscience volume 16, pages 1373–1382 (2013)Cite this article

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Abstract

Like all cancers, brain tumors require a continuous source of energy and molecular resources for new cell production. In normal brain, glucose is an essential neuronal fuel, but the blood-brain barrier limits its delivery. We now report that nutrient restriction contributes to tumor progression by enriching for brain tumor initiating cells (BTICs) owing to preferential BTIC survival and to adaptation of non-BTICs through acquisition of BTIC features. BTICs outcompete for glucose uptake by co-opting the high affinity neuronal glucose transporter, type 3 (Glut3, SLC2A3). BTICs preferentially express Glut3, and targeting Glut3 inhibits BTIC growth and tumorigenic potential. Glut3, but not Glut1, correlates with poor survival in brain tumors and other cancers; thus, tumor initiating cells may extract nutrients with high affinity. As altered metabolism represents a cancer hallmark, metabolic reprogramming may maintain the tumor hierarchy and portend poor prognosis.

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Figure 1: Glucose restriction promotes a brain tumor initiating cell phenotype.
Figure 2: Enrichment for BTICs under nutrient deprivation is associated with preferential BTIC survival and adaptation of non-BTICs toward a BTIC phenotype.
Figure 3: BTICs preferentially take up glucose.
Figure 4: Increased expression of Glut3 in BTICs drives glucose uptake.
Figure 5: Glut3 regulates BTIC growth and self-renewal.
Figure 6: GLUT3 expression is significantly increased in glioblastomas compared to lower grade tumors and in recurrent brain tumors and brain tumors from patients with poorer survival.
Figure 7: GLUT3 expression correlates with poor survival in multiple brain tumor data sets.
Figure 8: GLUT3 expression correlates with induced pluripotency and predicts poor survival in multiple tumor types beyond the brain.

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  • 12 September 2013

    In the version of this article initially published online, author Bryan W. Day did not appear. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank the Cleveland Clinic Foundation Tissue Procurement Service, S. Staugatis, M. McGraw, the Flow Cytometry Core, S. Bao, T. Miller, D. Schonberg and Monica Venere; and the US National Institutes of Health: CA129958, CA116659 and CA154130 (J.N.R.); CA151522 (A.B.H.); CA157948 (J.D.L.), CA137443, NS063971, CA128269, CA101954 and CA116257 (A.E.S.); James S. McDonnell Foundation (J.N.R.); Voices Against Brain Cancer (J.D.L.); Ohio Department of Development Tech 09-071 (A.E.S.); American Brain Tumor Association (Y.K.); and Melvin Burkhardt Chair in Neurosurgical Oncology and Karen Colina Wilson Research Endowment (R.J.W.).

Author information

Affiliations

  1. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio, USA

    William A Flavahan, Justin D Lathia, Jeremy N Rich & Anita B Hjelmeland

  2. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

    William A Flavahan, Qiulian Wu, Masahiro Hitomi, Nasiha Rahim, Youngmi Kim, Justin D Lathia, Jeremy N Rich & Anita B Hjelmeland

  3. Department of Neurological Surgery, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA

    Andrew E Sloan

  4. Department of Pathology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA

    Andrew E Sloan

  5. Department of Translational Neuroscience, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA

    Andrew E Sloan

  6. Department of Neurosurgery, the Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Robert J Weil

  7. Burkhardt Brain Tumor and Neuro-oncology Center, the Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Robert J Weil

  8. Department of Neurological Surgery, Dardinger Laboratory for Neurosciences, Ohio State University Medical Center, Columbus, Ohio, USA

    Ichiro Nakano

  9. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA

    Jann N Sarkaria

  10. Brain Cancer Research Unit and Leukaemia Foundation Research Unit, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    Brett W Stringer & Bryan W Day

  11. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Meizhang Li & Justin D Lathia

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Contributions

Conception and experimental design: W.A.F., Q.W., Y.K., J.D.L., J.N.R. and A.B.H. Methodology and data acquisition: W.A.F., Q.W., M.H., N.R., A.E.S., R.J.W., I.N., J.N.S., B.W.S., B.W.D., M.L., J.D.L. and A.B.H. Analysis and interpretation of data: W.A.F., M.H., M.L., J.D.L., J.N.R. and A.B.H. Manuscript writing and/or revision: W.A.F., J.N.R. and A.B.H.

Corresponding author

Correspondence to Jeremy N Rich.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary Figures 1–10 and Supplementary Tables 1–4 (PDF 8368 kb)

Glucose restriction induces Nanog promoter–driven GFP expression

Glucose restriction induces Nanog promoter–driven GFP expression (AVI 18523 kb)

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Flavahan, W., Wu, Q., Hitomi, M. et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16, 1373–1382 (2013). https://doi.org/10.1038/nn.3510

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