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 MukheefMinerva 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1893-1905.e7
JournalCell reports
Volume26
Issue number7
DOIs
StatePublished - Feb 12 2019

Funding

We thank the members of the Nakano and Bhat laboratories for their helpful suggestions. This work was supported by NIH/National Cancer Institute (NCI) grants P01 CA163205 and R21 CA175875 and NIH/National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS083767 and R01 NS087913, to I.N.; MD Anderson Institutional startup funds, the Sister Institution Network Fund from the Global Academic Programs, and an institutional research grant from the University Cancer Foundation, M.D. Anderson Cancer Center to K.P.B.; NIH CA158911, NS093843, NS095634, and R00LM011673, to S.L.; and Russian Foundation for Basic Research grants 17-29-06056 and 18-29-01027, to M.S.P. We would like to acknowledge the Department of Scientific Publications, University of Texas (UT) MD Anderson Cancer Center for proofreading the manuscript. We thank the members of the Nakano and Bhat laboratories for their helpful suggestions. This work was supported by NIH / National Cancer Institute (NCI) grants P01 CA163205 and R21 CA175875 and NIH / National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS083767 and R01 NS087913 , to I.N.; MD Anderson Institutional startup funds , the Sister Institution Network Fund from the Global Academic Programs , and an institutional research grant from the University Cancer Foundation , M.D. Anderson Cancer Center to K.P.B.; NIH CA158911 , NS093843 , NS095634 , and R00LM011673 , to S.L.; and Russian Foundation for Basic Research grants 17-29-06056 and 18-29-01027 , to M.S.P. We would like to acknowledge the Department of Scientific Publications, University of Texas (UT) MD Anderson Cancer Center for proofreading the manuscript.

Keywords

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

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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