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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Veröffentlicht in:	Cancer cell Jg. 32; H. 6; S. 856
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 11.12.2017
Schlagworte:	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
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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.
AbstractList	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.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. 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.
Author	Cosset, Érika Mischel, Paul S Cheresh, David A von Schalscha, Tami Camargo, Maria F Chneiweiss, Hervé Dietrich, Pierre-Yves Gomez, German Ilmjärv, Sten Elliott, Kathryn Seguin, Laetitia Moo, Jung-Soon Reiss, Alexander Moroishi, Toshiro Krause, Karl-Heinz Weis, Sara M Dutoit, Valérie Guan, Kun-Liang Preynat-Seauve, Olivier Sarkaria, Jann N
Author_xml	– sequence: 1 givenname: Érika surname: Cosset fullname: Cosset, Érika email: erika.cosset@unige.ch organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: erika.cosset@unige.ch – sequence: 2 givenname: Sten surname: Ilmjärv fullname: Ilmjärv, Sten organization: Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland – sequence: 3 givenname: Valérie surname: Dutoit fullname: Dutoit, Valérie organization: Laboratory of Tumor Immunology, Centre of Oncology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland – sequence: 4 givenname: Kathryn surname: Elliott fullname: Elliott, Kathryn organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 5 givenname: Tami surname: von Schalscha fullname: von Schalscha, Tami organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 6 givenname: Maria F surname: Camargo fullname: Camargo, Maria F organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 7 givenname: Alexander surname: Reiss fullname: Reiss, Alexander organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 8 givenname: Toshiro surname: Moroishi fullname: Moroishi, Toshiro organization: Department of Pharmacology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 9 givenname: Laetitia surname: Seguin fullname: Seguin, Laetitia organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 10 givenname: German surname: Gomez fullname: Gomez, German organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 11 givenname: Jung-Soon surname: Moo fullname: Moo, Jung-Soon organization: Department of Pharmacology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 12 givenname: Olivier surname: Preynat-Seauve fullname: Preynat-Seauve, Olivier organization: Division of Hematology, Departments of Internal Medicine and Human Protein Science, Faculty of Medicine, University of Geneva, Geneva, Switzerland – sequence: 13 givenname: Karl-Heinz surname: Krause fullname: Krause, Karl-Heinz organization: Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland – sequence: 14 givenname: Hervé surname: Chneiweiss fullname: Chneiweiss, Hervé organization: INSERM U1310, Sorbonne Universités, Paris, France – sequence: 15 givenname: Jann N surname: Sarkaria fullname: Sarkaria, Jann N organization: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA – sequence: 16 givenname: Kun-Liang surname: Guan fullname: Guan, Kun-Liang organization: Department of Pharmacology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 17 givenname: Pierre-Yves surname: Dietrich fullname: Dietrich, Pierre-Yves organization: Laboratory of Tumor Immunology, Centre of Oncology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland – sequence: 18 givenname: Sara M surname: Weis fullname: Weis, Sara M organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA – sequence: 19 givenname: Paul S surname: Mischel fullname: Mischel, Paul S organization: Ludwig Institute for Cancer Research, Department of Pathology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA – sequence: 20 givenname: David A surname: Cheresh fullname: Cheresh, David A email: dcheresh@ucsd.edu organization: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: dcheresh@ucsd.edu
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SubjectTerms	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
Title	Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma
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