Levels of the proneural-associated gene OLIG2 determine glioma phenotype and regulate cell growth.

  • Major finding: Levels of the proneural-associated gene OLIG2 determine glioma phenotype and regulate cell growth.

  • Mechanism: OLIG2 upregulates cell growth genes and inhibits classical GBM signature genes.

  • Impact: Inhibition of OLIG2 may overcome resistance to anti-EGFR treatment.

Glioblastomas (GBM), which are the most common adult brain malignancy and are highly heterogeneous, can be subdivided into four molecular subtypes with distinct genetic alterations: proneural, classic, neural, and mesenchymal. However, GBM tumor cells have been found to exhibit phenotypic plasticity in switching from proneural GBMs, which are transcriptionally similar to oligodendrocyte precursor cells (OPC) and exhibit PDGFRA amplification, to mesenchymal GBMs. Lu and colleagues evaluated the role of OLIG2, a marker of OPCs and one of a set of factors that induces a stemlike state in differentiated GBM cells, in gliomagenesis and showed that mitotic progenitors in human gliomas with PDGFRA amplification and tumors from a mouse model of proneural glioma exhibited elevated OLIG2 expression. Depletion of Olig2+ proliferative cells in proneural glioma-bearing mice resulted in decreased glioma formation and increased survival. Consistent with these results, Olig2-deleted murine proneural glioma cells retained their tumorigenic capacity but exhibited decreased in vivo glioma growth and in vitro formation of neurospheres. Transcriptomic profiling and chromatin immunoprecipitation sequencing revealed that Olig2 directly targeted enhancers of genes encoding regulators of cell growth and oncogenes and upregulated expression of these genes, and that Olig2 negatively regulated the expression of genes associated with classic glioma, such as Egfr. Knockdown of OLIG2 resulted in a shift from the proneural gene signature to the classic gene signature. Treatment with EGFR inhibitors reduced growth of Olig2-deleted glioma but not Olig2+ glioma in vitro and increased survival of Olig2 knockout mice but not Olig2 wild-type tumor-forming mice. Taken together, these results show that OLIG2 is critical for proneural glioma cell mitotic growth and mediates glioma phenotype switching, and that targeting OLIG2 may enhance anti-EGFR therapies.

Lu F, Chen Y, Zhao C, Wang H, He D, Xu L, et al. Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell 2016;29:669–83.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.