Παρασκευή 1 Δεκεμβρίου 2017

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

Publication date: Available online 30 November 2017
Source:Cancer Cell
Author(s): 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
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.

Graphical abstract

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Teaser

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.


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