Oligodendroglioma is a low-grade primary brain tumour predicted to originate from mutations in neural stem and/or progenitor cells (NSPCs). Loss of tumour suppressors CIC and FUBP1 significantly co-occur and are among the most frequent genetic lesions in oligodendroglioma. We predict that loss-of-function of the transcriptional repressor CIC, and the single-stranded nucleic acid binding protein FUBP1, drive oligodendroglioma, most likely by rewiring the transcriptome to impair NSPC differentiation programs.
Intra-tumour cell interactions, particularly between glioma-driving NSPCs and surrounding mutant glial populations, undoubtedly drive oligodendroglioma; yet the signalling networks involved are unknown. Thus, to identify networks dysregulated by oligodendroglioma driver mutations, we developed models for manipulation of Cic (CIC) and Psi (FUBP1) specifically in the glia supporting NSPCs in the developing Drosophila brain.
We demonstrate knockdown of Cic or Psi specifically in the cortex glia of the larval brain, either alone or in combination, is sufficient to drive expansion of neighbouring neural stem cells (NSCs). Excitingly, cortex glial-specific genome-wide binding analysis (via Targeted DamID) for Psi and Cic, combined with expression studies (RNA-seq for Cic or Psi knockdown vs control), revealed that these transcriptional regulators control signalling between the glial niche and NSCs. Specifically, we have identified secreted factors (e.g. EGFR and FGFR ligands) and major developmental signalling pathways (e.g. Notch and Hippo) as directly dysregulated targets of Cic and/or Psi. Using single cell RNA-seq (scRNAseq) we will determine alterations to the cortex glial cell niche and associated NSPC transcriptomes, to elucidate mechanisms for non-autonomous control of NSPC fate by Psi and Cic.
Together, our data demonstrate FUBP1/Psi and CIC/Cic function cell non-autonomously in the glial niche to structurally support and regulate the signalling networks fundamental to NSC renewal and differentiation. As brain cancer is driven by glioma stem cells residing in a tumour mass largely comprised of glia, our studies may inform inter-tumour signalling defects of significance to FUBP1/CIC-driven oligodendroglioma.