A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR

Talal F. Al-Mayhani, Richard M. Heywood, Vamsidhara Vemireddy, Justin D. Lathia, Sara Grazia Maria Piccirillo, Colin Watts

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

BACKGROUND: Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2- cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. METHODS: Single GBM NG2+ and NG2- cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2- cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. RESULTS: Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2- or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. CONCLUSIONS: These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2- cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

Original languageEnglish (US)
Pages (from-to)719-729
Number of pages11
JournalNeuro-oncology
Volume21
Issue number6
DOIs
StatePublished - Jun 10 2019

Fingerprint

Glioblastoma
Epidermal Growth Factor Receptor
Neuroglia
Neurons
Antigens
Phenotype

Keywords

  • EGFR signaling
  • glioblastoma
  • NG2

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Al-Mayhani, T. F., Heywood, R. M., Vemireddy, V., Lathia, J. D., Piccirillo, S. G. M., & Watts, C. (2019). A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR. Neuro-oncology, 21(6), 719-729. https://doi.org/10.1093/neuonc/noy204

A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR. / Al-Mayhani, Talal F.; Heywood, Richard M.; Vemireddy, Vamsidhara; Lathia, Justin D.; Piccirillo, Sara Grazia Maria; Watts, Colin.

In: Neuro-oncology, Vol. 21, No. 6, 10.06.2019, p. 719-729.

Research output: Contribution to journalArticle

Al-Mayhani, TF, Heywood, RM, Vemireddy, V, Lathia, JD, Piccirillo, SGM & Watts, C 2019, 'A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR', Neuro-oncology, vol. 21, no. 6, pp. 719-729. https://doi.org/10.1093/neuonc/noy204
Al-Mayhani TF, Heywood RM, Vemireddy V, Lathia JD, Piccirillo SGM, Watts C. A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR. Neuro-oncology. 2019 Jun 10;21(6):719-729. https://doi.org/10.1093/neuonc/noy204
Al-Mayhani, Talal F. ; Heywood, Richard M. ; Vemireddy, Vamsidhara ; Lathia, Justin D. ; Piccirillo, Sara Grazia Maria ; Watts, Colin. / A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR. In: Neuro-oncology. 2019 ; Vol. 21, No. 6. pp. 719-729.
@article{d5987454295d422eb2990e13d2ea517f,
title = "A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR",
abstract = "BACKGROUND: Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2- cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. METHODS: Single GBM NG2+ and NG2- cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2- cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. RESULTS: Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2- or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. CONCLUSIONS: These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2- cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.",
keywords = "EGFR signaling, glioblastoma, NG2",
author = "Al-Mayhani, {Talal F.} and Heywood, {Richard M.} and Vamsidhara Vemireddy and Lathia, {Justin D.} and Piccirillo, {Sara Grazia Maria} and Colin Watts",
year = "2019",
month = "6",
day = "10",
doi = "10.1093/neuonc/noy204",
language = "English (US)",
volume = "21",
pages = "719--729",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR

AU - Al-Mayhani, Talal F.

AU - Heywood, Richard M.

AU - Vemireddy, Vamsidhara

AU - Lathia, Justin D.

AU - Piccirillo, Sara Grazia Maria

AU - Watts, Colin

PY - 2019/6/10

Y1 - 2019/6/10

N2 - BACKGROUND: Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2- cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. METHODS: Single GBM NG2+ and NG2- cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2- cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. RESULTS: Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2- or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. CONCLUSIONS: These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2- cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

AB - BACKGROUND: Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2- cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. METHODS: Single GBM NG2+ and NG2- cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2- cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. RESULTS: Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2- or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. CONCLUSIONS: These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2- cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

KW - EGFR signaling

KW - glioblastoma

KW - NG2

UR - http://www.scopus.com/inward/record.url?scp=85067619549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067619549&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noy204

DO - 10.1093/neuonc/noy204

M3 - Article

C2 - 30590711

AN - SCOPUS:85067619549

VL - 21

SP - 719

EP - 729

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 6

ER -