Nissen, I.; Dakhel, S.; Chakraborty, C.; Nygaard, A. H.; Kirkeby, A.; Hornblad, A.; Erdem, C.; Remeseiro, S.

Gene regulatory networks (GRNs) are essential for precise control of gene expression, orchestrating cellular functions by coordinating interactions between transcription factors (TFs), enhancers, and gene promoters. Disruptions in these regulatory networks are known to contribute to oncogenic processes, particularly because of alterations in epigenetic modifications, chromatin accessibility and promoter-enhancer interactions within the 3D nucleus. Here, we integrated multi-omics datasets using the machine learning-based MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) pipeline to uncover novel GRNs and pathways involved in glioblastoma (GB) pathogenesis, one of the most aggressive brain cancers. GABA-signalling emerged as a previously unrecognized potential driver of GB tumour pathogenesis, with the discovery of GABA-related networks and relevant transcription factors (TFs) such as ARX, GSX2 and members of the DLX family, which play key roles in GABAergic interneuron development. Furthermore, in vitro co-culture assays showed that GABAergic input promotes GB cell proliferation, potentially through non-synaptic pathways such as metabolic or paracrine mechanisms. Our study provides insights into novel GRNs in GB pathogenesis, positioning GABA signalling as a potential therapeutic vulnerability in GB, and offering new promising therapeutic targets aimed at blocking neuron-glioma interactions.