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 subtype
• tumor phenotype plasticity

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors would like to Ravinder Verma for providing unpublished information, Rohit Rao for contribution in initial manuscript preparation, and Edward Hurlock for critical comments.

Funding

This study was funded in part by grants from the Mayfield Education and Research Foundation to JK and Molecular Therapeutics Program to QRL, and the US National Institutes of Health (R01 NS078092) to QRL and (R01 NS088648) to SM.