Gliomas comprise 80% of primary brain tumours, yet new therapies to improve patient outcomes haven’t reached clinic in over 30 years. Although cancer stem cells are predicted to promote brain tumour initiation, progression, and recurrence, we currently do not understand interactions between glioma stem cells and the surrounding neural microenvironment, or niche. Furthermore, despite the extensive catalogue of brain cancer mutations (e.g. The Cancer Genome Atlas), we lack functional genetic data for glioma drivers predicted by GWAS. For example, the HMG-box transcriptional repressor CIC is mutated in oligodendroglioma, but mechanisms of tumour suppression remain obscure.
As CIC is highly conserved, being first identified as a transcriptional repressor downstream of receptor tyrosine kinases in the Drosophila embryo, we developed genetic models for manipulation of Cic specifically in the cortex glia comprising the neural stem cell (NSC) niche. Our exciting preliminary data demonstrates Cic knockdown (KD) specifically in the niche drives overproliferation of the neighbouring NSCs. To determine the molecular basis of the non-autonomous requirement for Cic in the niche, we identified genome-wide binding targets for Cic specifically for the cortex glia, and the Cic KD transcriptome in the niche and neighbouring NSCs. Direct differentially expressed Cic targets included factors implicated in cell-cell communication, including ligands for receptor-mediated signalling e.g. EGF and FGF. Moreover, we observed significant dysregulation of the transcriptome for NSCs associated with Cic-depleted glia, with upregulation of genes driving renewal and downregulation of neuronal differentiation factors. Thus, Cic function in the cortex glial niche is essential for driving NSC differentiation. As Cic is highly conserved, our studies will provide insight into interactions between glioma stem cells and neighbouring glia of significance to CIC’s predicted tumour suppressor function in glioma.