Cell Reports (May 2015)
Differential Connexin Function Enhances Self-Renewal in Glioblastoma
- Masahiro Hitomi,
- Loic P. Deleyrolle,
- Erin E. Mulkearns-Hubert,
- Awad Jarrar,
- Meizhang Li,
- Maksim Sinyuk,
- Balint Otvos,
- Sylvain Brunet,
- William A. Flavahan,
- Christopher G. Hubert,
- Winston Goan,
- James S. Hale,
- Alvaro G. Alvarado,
- Ao Zhang,
- Mark Rohaus,
- Muna Oli,
- Vinata Vedam-Mai,
- Jeff M. Fortin,
- Hunter S. Futch,
- Benjamin Griffith,
- Qiulian Wu,
- Chun-hong Xia,
- Xiaohua Gong,
- Manmeet S. Ahluwalia,
- Jeremy N. Rich,
- Brent A. Reynolds,
- Justin D. Lathia
Affiliations
- Masahiro Hitomi
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Loic P. Deleyrolle
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Erin E. Mulkearns-Hubert
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Awad Jarrar
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Meizhang Li
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Maksim Sinyuk
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Balint Otvos
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Sylvain Brunet
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- William A. Flavahan
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Christopher G. Hubert
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Winston Goan
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- James S. Hale
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Alvaro G. Alvarado
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Ao Zhang
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Mark Rohaus
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Muna Oli
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Vinata Vedam-Mai
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Jeff M. Fortin
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Hunter S. Futch
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Benjamin Griffith
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Qiulian Wu
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- Chun-hong Xia
- Berkeley Stem Cell Center, University of California, Berkeley, Berkeley, CA 94720, USA
- Xiaohua Gong
- Berkeley Stem Cell Center, University of California, Berkeley, Berkeley, CA 94720, USA
- Manmeet S. Ahluwalia
- Rose Ella Burkhardt Brain Tumor and Neuro Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA
- Jeremy N. Rich
- Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
- Brent A. Reynolds
- Department of Neurosurgery, University of Florida, Gainesville, FL 32610-0261, USA
- Justin D. Lathia
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.04.021
- Journal volume & issue
-
Vol. 11,
no. 7
pp. 1031 – 1042
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.
