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

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 complic...

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Published in:Cancer cell Vol. 32; no. 6; p. 856
Main Authors: Cosset, Érika, Ilmjärv, Sten, Dutoit, Valérie, Elliott, Kathryn, von Schalscha, Tami, Camargo, Maria F, Reiss, Alexander, Moroishi, Toshiro, Seguin, Laetitia, Gomez, German, Moo, Jung-Soon, Preynat-Seauve, Olivier, Krause, Karl-Heinz, Chneiweiss, Hervé, Sarkaria, Jann N, Guan, Kun-Liang, Dietrich, Pierre-Yves, Weis, Sara M, Mischel, Paul S, Cheresh, David A
Format: Journal Article
Language:English
Published: United States 11.12.2017
Subjects:
Animals
Antineoplastic Agents - pharmacology
Brain Neoplasms - metabolism
Brain Neoplasms - mortality
Cell Line, Tumor
Gene Expression Profiling
Glioblastoma - metabolism
Glioblastoma - mortality
Glucose Transporter Type 3 - metabolism
Humans
Integrin alphaVbeta3 - metabolism
Kaplan-Meier Estimate
Mice
Mice, Nude
Signal Transduction
Snake Venoms - pharmacology
Transcriptome
Xenograft Model Antitumor Assays
glioblastoma
cancer stem cells
Glut3
integrin
glucose metabolism
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary: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.
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2017.10.016