Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma

• Published in: Cancer cell Vol. 29; no. 5; pp. 669 - 683
• Main Authors: Lu, Fanghui, Chen, Ying, Zhao, Chuntao, Wang, Haibo, He, Danyang, Xu, Lingli, Wang, Jincheng, He, Xuelian, Deng, Yaqi, Lu, Ellen E., Liu, Xue, Verma, Ravinder, Bu, Hong, Drissi, Rachid, Fouladi, Maryam, Stemmer-Rachamimov, Anat O., Burns, Dennis, Xin, Mei, Rubin, Joshua B., Bahassi, El Mustapha, Canoll, Peter, Holland, Eric C., Lu, Q. Richard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.05.2016
• Subjects: Animals; Astrocytes - metabolism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Line, Tumor; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oligodendroglia - metabolism; Phenotype; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptors, Platelet-Derived Growth Factor - genetics; Receptors, Platelet-Derived Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Spheroids, Cellular - metabolism; Survival Analysis
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.03.027

Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs. [Display omitted] •Elimination of mitotic Olig2+ cells inhibits glioma initiation and progression•Olig2 loss reduces glioma growth and causes proneural-to-astrocytic phenotype shift•Olig2 deletion causes PDGFR downregulation and reciprocal EGFR upregulation•Inactivation of Olig2 potentiates sensitization of glioma cells to EGFR inhibition Lu et al. show that ablation of dividing Olig2-expressing cells in a glioma model reduces tumor initiation and growth. Olig2 deletion in glioma also delays growth, changes the gene expression profile from proneural to astrocyte-associated classical phenotype, and leads to increased EGFR expression and sensitivity to EGFR inhibitors.