title: Differential connexin function enhances self-renewal in glioblastoma.
abstract: The coordination of complex tumor processes requires cells to rapidly modify their phenotype and is achieved by direct cell-cell communication through gap junction channels composed of connexins. Previous reports have suggested that gap junctions are tumor suppressive based on connexin 43 (Cx43), but this does not take into account differences in connexin-mediated ion selectivity and intercellular communication rate that drive gap junction diversity. We find that glioblastoma cancer stem cells (CSCs) possess functional gap junctions that can be targeted using clinically relevant compounds to reduce self-renewal and tumor growth. Our analysis reveals that CSCs express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance. The difference between Cx46 and Cx43 is reflected in elevated cell-cell communication and reduced resting membrane potential in CSCs. Our data demonstrate a pro-tumorigenic role for gap junctions that is dependent on connexin expression.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Loic P
authors.initials: LP
authors.lastname: Deleyrolle
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulkearns-Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Awad
authors.initials: A
authors.lastname: Jarrar
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Meizhang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Balint
authors.initials: B
authors.lastname: Otvos
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brunet
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Goan
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Rohaus
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Muna
authors.initials: M
authors.lastname: Oli
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Vinata
authors.initials: V
authors.lastname: Vedam-Mai
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Fortin
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Hunter S
authors.initials: HS
authors.lastname: Futch
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Griffith
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Berkeley Stem Cell Center, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Xia
authors.affiliation: Berkeley Stem Cell Center, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gong
authors.affiliation: Rose Ella Burkhardt Brain Tumor and Neuro Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.affiliation: Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Rose Ella Burkhardt Brain Tumor and Neuro Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA. Electronic address: brent.reynolds@neurosurgery.ufl.edu.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Rose Ella Burkhardt Brain Tumor and Neuro Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. Electronic address: lathiaj@ccf.org.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D018031:Connexin 43 / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008564:Membrane Potentials / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction
chemical_list: D018031:Connexin 43; D017630:Connexins; C500216:GJA1 protein, human; C082917:GJA3 protein, human