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Cell Rep. 2019 Feb 12;26(7):1893-1905.e7. doi: 10.1016/j.celrep.2019.01.076.

Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation.

Author information

1
Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA.
2
Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
4
Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
5
Medical Scientist Training Program, The University of Alabama at Birmingham, Birmingham, AL, USA.
6
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation.
7
Department of Animal Science, Chonnam National University, Gwangju 61186, Korea.
8
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.
9
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.
10
Department of Biology, Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA.
11
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China; Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
12
Department of Surgery, The Ohio State University, Columbus, OH, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
13
Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
14
Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
15
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
16
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.
17
Experimental Therapeutics and Molecular Imaging Lab, Department of Neurology, Neuro-oncology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
18
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.
19
Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: inakano@uabmc.edu.
20
Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: kbhat@mdanderson.org.

Abstract

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.

KEYWORDS:

CD109; CD133; glioblastoma; glioma stem-like cells; mesenchymal differentiation; radioresistance

PMID:
30759398
DOI:
10.1016/j.celrep.2019.01.076
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