Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

Érika Cosset, Sten Ilmjärv, Valérie Dutoit, Kathryn Elliott, Tami von Schalscha, Maria F. Camargo, Alexander Reiss, Toshiro Moroishi, Laetitia Seguin, German Gomez, Jung Soon Moo, Olivier Preynat-Seauve, Karl Heinz Krause, Hervé Chneiweiss, Jann N. Sarkaria, Kun Liang Guan, Pierre Yves Dietrich, Sara M. Weis, Paul S. Mischel, David A. Cheresh

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the “proneural” and “classical” subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors. Cosset et al. identify a subset of glioblastoma within the proneural and the classical subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression, and are sensitive to agents disrupting the pathway such as cilengitide.

Original languageEnglish (US)
Pages (from-to)856-868.e5
JournalCancer cell
Volume32
Issue number6
DOIs
StatePublished - Dec 11 2017

Keywords

  • Glut3
  • cancer stem cells
  • glioblastoma
  • glucose metabolism
  • integrin

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Cosset, É., Ilmjärv, S., Dutoit, V., Elliott, K., von Schalscha, T., Camargo, M. F., Reiss, A., Moroishi, T., Seguin, L., Gomez, G., Moo, J. S., Preynat-Seauve, O., Krause, K. H., Chneiweiss, H., Sarkaria, J. N., Guan, K. L., Dietrich, P. Y., Weis, S. M., Mischel, P. S., & Cheresh, D. A. (2017). Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. Cancer cell, 32(6), 856-868.e5. https://doi.org/10.1016/j.ccell.2017.10.016