Gliomas comprise 80% of all primary brain tumours and despite decades of study, no new therapies or improved outcomes for glioma patients have emerged in >30 years. While cancer stem cells are predicted to promote brain tumour initiation, progression and recurrence, a major gap in our understanding of glioma is the interaction between cancer stem cells and the tumour-promoting microenvironment (niche). Furthermore, although an extensive catalogue of brain cancer mutations has been developed by The Cancer Genome Atlas (TCGA), functional data to determine whether these mutations drive glioma is lacking. Among the genes most frequently mutated in low grade glioma is CIC, an HMG-box transcriptional repressor. Cic was first identified in Drosophila where it functions downstream of receptor tyrosine kinases to inhibit proliferation and control development. However, the functions of CIC in the brain and its potential roles in glioma are poorly understood.
The Drosophila larval brain provides a sophisticated model for detailed in vivo genetic studies of the neural stem cell lineage in context with the surrounding glial microenvironment. We modelled CIC loss-of-function by depleting Cic specifically in the cortex glia of the larval brain. Strikingly, our data demonstrates that Cic is required in the glial niche to non-autonomously prevent expansion of the neural stem cells. Transcriptome analysis revealed numerous differentially expressed genes in the cortex glia upon Cic knockdown, and in neural stem cells associated with Cic-depleted cortex glia. Loss of Cic in the cortex glia cell-intrinsically resulted in dysregulation of cellular metabolism, EGFR signalling and cell adhesion. Furthermore, Cic depletion in the glia non-autonomously resulted in upregulation of mitotic cell cycle and downregulation of neuronal differentiation in neural stem cells. Thus, our data implicates Cic in the non-autonomous control of neural stem cell fate from the niche, providing insights into tumorigenic functions of CIC in glioma.