Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas

Jennifer Kosty, Fanghui Lu, Robert Kupp, Shwetal Mehta, Q. Richard Lu

Research output: Contribution to journalComment/debate

2 Citations (Scopus)

Abstract

Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.

Original languageEnglish (US)
Pages (from-to)1654-1660
Number of pages7
JournalCell Cycle
Volume16
Issue number18
DOIs
StatePublished - Sep 17 2017

Fingerprint

Glioma
Stem Cells
Glioblastoma
Neoplasms
Growth
Down-Regulation
Animal Models
Basic Helix-Loop-Helix Transcription Factors
Phenotype
Cell Line
Genetic Heterogeneity
Neoplastic Stem Cells
Post Translational Protein Processing
Brain Neoplasms
Protein Kinases
Molecular Biology
Up-Regulation
Therapeutics
Phosphorylation
Gene Expression

Keywords

  • classical
  • GBM stem cells
  • glioblastoma
  • glioma model
  • mesenchymal
  • OLIG2
  • proneural
  • transcriptome analysis
  • tumor phenotype plasticity
  • tumor subtype

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas. / Kosty, Jennifer; Lu, Fanghui; Kupp, Robert; Mehta, Shwetal; Lu, Q. Richard.

In: Cell Cycle, Vol. 16, No. 18, 17.09.2017, p. 1654-1660.

Research output: Contribution to journalComment/debate

Kosty, Jennifer ; Lu, Fanghui ; Kupp, Robert ; Mehta, Shwetal ; Lu, Q. Richard. / Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas. In: Cell Cycle. 2017 ; Vol. 16, No. 18. pp. 1654-1660.
@article{19531dd978c644e981265d163fc14a7f,
title = "Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas",
abstract = "Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.",
keywords = "classical, GBM stem cells, glioblastoma, glioma model, mesenchymal, OLIG2, proneural, transcriptome analysis, tumor phenotype plasticity, tumor subtype",
author = "Jennifer Kosty and Fanghui Lu and Robert Kupp and Shwetal Mehta and Lu, {Q. Richard}",
year = "2017",
month = "9",
day = "17",
doi = "10.1080/15384101.2017.1361062",
language = "English (US)",
volume = "16",
pages = "1654--1660",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "18",

}

TY - JOUR

T1 - Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas

AU - Kosty, Jennifer

AU - Lu, Fanghui

AU - Kupp, Robert

AU - Mehta, Shwetal

AU - Lu, Q. Richard

PY - 2017/9/17

Y1 - 2017/9/17

N2 - Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.

AB - Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.

KW - classical

KW - GBM stem cells

KW - glioblastoma

KW - glioma model

KW - mesenchymal

KW - OLIG2

KW - proneural

KW - transcriptome analysis

KW - tumor phenotype plasticity

KW - tumor subtype

UR - http://www.scopus.com/inward/record.url?scp=85028879602&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028879602&partnerID=8YFLogxK

U2 - 10.1080/15384101.2017.1361062

DO - 10.1080/15384101.2017.1361062

M3 - Comment/debate

VL - 16

SP - 1654

EP - 1660

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 18

ER -