Cell Reports (Feb 2019)
Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation
- Mutsuko Minata,
- Alessandra Audia,
- Junfeng Shi,
- Songjian Lu,
- Joshua Bernstock,
- Marat S. Pavlyukov,
- Arvid Das,
- Sung-Hak Kim,
- Yong Jae Shin,
- Yeri Lee,
- Harim Koo,
- Kirti Snigdha,
- Indrayani Waghmare,
- Xing Guo,
- Ahmed Mohyeldin,
- Daniel Gallego-Perez,
- Jia Wang,
- Dongquan Chen,
- Peng Cheng,
- Farah Mukheef,
- Minerva Contreras,
- Joel F. Reyes,
- Brian Vaillant,
- Erik P. Sulman,
- Shi-Yuan Cheng,
- James M. Markert,
- Bakhos A. Tannous,
- Xinghua Lu,
- Madhuri Kango-Singh,
- L. James Lee,
- Do-Hyun Nam,
- Ichiro Nakano,
- Krishna P. Bhat
Affiliations
- Mutsuko Minata
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
- Alessandra Audia
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Junfeng Shi
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
- Songjian Lu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Joshua Bernstock
- Medical Scientist Training Program, The University of Alabama at Birmingham, Birmingham, AL, USA
- Marat S. Pavlyukov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation
- Arvid Das
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Sung-Hak Kim
- Department of Animal Science, Chonnam National University, Gwangju 61186, Korea
- Yong Jae Shin
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, Korea
- Yeri Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Harim Koo
- Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Kirti Snigdha
- Department of Biology, Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA
- Indrayani Waghmare
- Department of Biology, Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA
- Xing Guo
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China; Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Ahmed Mohyeldin
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
- Daniel Gallego-Perez
- Department of Surgery, The Ohio State University, Columbus, OH, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
- Jia Wang
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
- Dongquan Chen
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
- Peng Cheng
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
- Farah Mukheef
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Minerva Contreras
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Joel F. Reyes
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Brian Vaillant
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Erik P. Sulman
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Shi-Yuan Cheng
- The Ken & Ruth Davee Department of Neurology & Northwestern Brain Tumor Institute, Center for Genetic Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- James M. Markert
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
- Bakhos A. Tannous
- Experimental Therapeutics and Molecular Imaging Lab, Department of Neurology, Neuro-oncology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Xinghua Lu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Madhuri Kango-Singh
- Department of Biology, Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA
- L. James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
- Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, Korea
- Ichiro Nakano
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author
- Krishna P. Bhat
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
- Journal volume & issue
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Vol. 26,
no. 7
pp. 1893 – 1905.e7
Abstract
Summary: Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133−/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM. : Minata et al., in response to the proinflammatory environment induced by radiation, find that the tumor cells at the invasive edge acquire the expression of the CD109 protein concomitantly losing CD133. CD109 drives oncogenic signaling through the YAP/TAZ pathway, confers radioresistance to the cells, and represents a new potential therapeutic target for glioblastoma. Keywords: glioblastoma, glioma stem-like cells, mesenchymal differentiation, CD109, CD133, radioresistance
