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 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.
Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Robert
R
Kupp
Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Lior
L
Shtayer
Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
An-Chi
AC
Tien
Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Emily
E
Szeto
Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Nader
N
Sanai
Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Wellcome Trust-MRC Stem Cell Institute and Department of Pediatrics, University of Cambridge, Cambridge CB2 0AH, UK.
David H
DH
Rowitch
Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: shwetal.mehta@dignityhealth.org.
Shwetal
S
Mehta
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D000076104:Oligodendrocyte Transcription Factor 2; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; C512773:Olig2 protein, mouse
Olig2; cancer stem cell; glioblastoma; growth factor; receptor tyrosine kinase