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

doi:10.1016/j.celrep.2019.01.076

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

Neurology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	1893-1905.e7
Journal	Cell reports
Volume	26
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2019.01.076
State	Published - 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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10.1016/j.celrep.2019.01.076

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Minata, M., Audia, A., Shi, J., Lu, S., Bernstock, J., Pavlyukov, M. S., Das, A., Kim, S. H., Shin, Y. J., Lee, Y., Koo, H., Snigdha, K., Waghmare, I., Guo, X., Mohyeldin, A., Gallego-Perez, D., Wang, J., Chen, D., Cheng, P., ... Bhat, K. P. (2019). Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation. Cell reports, 26(7), 1893-1905.e7. https://doi.org/10.1016/j.celrep.2019.01.076

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title = "Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation",

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",

author = "Mutsuko Minata and Alessandra Audia and Junfeng Shi and Songjian Lu and Joshua Bernstock and Pavlyukov, {Marat S.} and Arvid Das and Kim, {Sung Hak} and Shin, {Yong Jae} and Yeri Lee and Harim Koo and Kirti Snigdha and Indrayani Waghmare and Xing Guo and Ahmed Mohyeldin and Daniel Gallego-Perez and Jia Wang and Dongquan Chen and Peng Cheng and Farah Mukheef and Minerva Contreras and Reyes, {Joel F.} and Brian Vaillant and Sulman, {Erik P.} and Cheng, {Shi Yuan} and Markert, {James M.} and Tannous, {Bakhos A.} and Xinghua Lu and Madhuri Kango-Singh and Lee, {L. James} and Nam, {Do Hyun} and Ichiro Nakano and Bhat, {Krishna P.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = feb,

day = "12",

doi = "10.1016/j.celrep.2019.01.076",

language = "English (US)",

volume = "26",

pages = "1893--1905.e7",

journal = "Cell reports",

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Minata, M, Audia, A, Shi, J, Lu, S, Bernstock, J, Pavlyukov, MS, Das, A, Kim, SH, Shin, YJ, Lee, Y, Koo, H, Snigdha, K, Waghmare, I, Guo, X, Mohyeldin, A, Gallego-Perez, D, Wang, J, Chen, D, Cheng, P, Mukheef, F, Contreras, M, Reyes, JF, Vaillant, B, Sulman, EP, Cheng, SY, Markert, JM, Tannous, BA, Lu, X, Kango-Singh, M, Lee, LJ, Nam, DH, Nakano, I & Bhat, KP 2019, 'Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation', Cell reports, vol. 26, no. 7, pp. 1893-1905.e7. https://doi.org/10.1016/j.celrep.2019.01.076

TY - JOUR

T1 - Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation

AU - Minata, Mutsuko

AU - Audia, Alessandra

AU - Shi, Junfeng

AU - Lu, Songjian

AU - Bernstock, Joshua

AU - Pavlyukov, Marat S.

AU - Das, Arvid

AU - Kim, Sung Hak

AU - Shin, Yong Jae

AU - Lee, Yeri

AU - Koo, Harim

AU - Snigdha, Kirti

AU - Waghmare, Indrayani

AU - Guo, Xing

AU - Mohyeldin, Ahmed

AU - Gallego-Perez, Daniel

AU - Wang, Jia

AU - Chen, Dongquan

AU - Cheng, Peng

AU - Mukheef, Farah

AU - Contreras, Minerva

AU - Reyes, Joel F.

AU - Vaillant, Brian

AU - Sulman, Erik P.

AU - Cheng, Shi Yuan

AU - Markert, James M.

AU - Tannous, Bakhos A.

AU - Lu, Xinghua

AU - Kango-Singh, Madhuri

AU - Lee, L. James

AU - Nam, Do Hyun

AU - Nakano, Ichiro

AU - Bhat, Krishna P.

PY - 2019/2/12

Y1 - 2019/2/12

N2 - 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.

AB - 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.

KW - CD109

KW - CD133

KW - glioblastoma

KW - glioma stem-like cells

KW - mesenchymal differentiation

KW - radioresistance

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UR - http://www.scopus.com/inward/citedby.url?scp=85061123030&partnerID=8YFLogxK

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DO - 10.1016/j.celrep.2019.01.076

M3 - Article

C2 - 30759398

AN - SCOPUS:85061123030

SN - 2211-1247

VL - 26

SP - 1893-1905.e7

JO - Cell reports

JF - Cell reports

IS - 7

ER -

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

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