Title

Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells

Document Type

Article

Abstract

The basic helix-loop-helix (bHLH) transcription factor OLIG2 is a master regulator of oligodendroglial fate decisions and tumorigenic competence of glioma stem-like cells (GSCs). However, the molecular mechanisms underlying dysregulation of OLIG2 function during gliomagenesis remains poorly understood. Here, we show that OLIG2 modulates growth factor signaling in two distinct populations of GSCs, characterized by expression of either the epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRα). Biochemical analyses of OLIG2 function in normal and malignant neural progenitors reveal a positive feedforward loop between OLIG2 and EGFR to sustain co-expression. Furthermore, loss of OLIG2 function results in mesenchymal transformation in PDGFRα(HIGH) GSCs, a phenomenon that appears to be circumscribed in EGFR(HIGH) GSCs. Exploitation of OLIG2's dual and antithetical, pro-mitotic (EGFR-driven), and lineage-specifying (PDGFRα-driven) functions by glioma cells appears to be critical for sustaining growth factor signaling and GSC molecular subtype.

Keywords

Olig2, cancer stem cell, glioblastoma, growth factor, receptor tyrosine kinase

Medical Subject Headings

Animals; Basic Helix-Loop-Helix Transcription Factors (metabolism); Brain Neoplasms (metabolism, pathology); Cell Cycle; Cell Lineage; Cell Nucleus (metabolism); ErbB Receptors (metabolism); Glioma (metabolism, pathology); Humans; Intercellular Signaling Peptides and Proteins (metabolism); Mesoderm (metabolism); Mice; Neoplastic Stem Cells (metabolism, pathology); Nerve Tissue Proteins (metabolism); Neural Stem Cells (metabolism, pathology); Oligodendrocyte Transcription Factor 2; Phosphorylation; Receptor Protein-Tyrosine Kinases (metabolism); Receptors, Platelet-Derived Growth Factor (metabolism); Signal Transduction

Publication Date

9-13-2016

Publication Title

Cell reports

E-ISSN

2211-1247

Volume

16

Issue

11

First Page

2838

Last Page

2845

PubMed ID

27626655

Digital Object Identifier (DOI)

10.1016/j.celrep.2016.08.040

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