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

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 PDGFRαHIGH GSCs, a phenomenon that appears to be circumscribed in EGFRHIGH 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. [Display omitted] •OLIG2 forms a feedforward loop with mitogenic signaling in neural progenitors•Inhibition of EGFR results in depletion of OLIG2 protein•Phosphorylation state of OLIG2 alters expression of RTKs•Loss of OLIG2 function in GSCs results in mesenchymal transformation Kupp et al. find that the CNS-restricted transcription factor OLIG2 acts as a critical mediator of growth factor signaling in normal and malignant neural progenitors. Abrogation of OLIG2 function impairs expression of EGFR and PDGFRα, the two most commonly dysregulated growth factor receptors in malignant gliomas.