Gene regulatory networks linked to GABA signalling emerge as relevant for glioblastoma pathogenesis

Glioblastoma (GB) is the most common and aggressive adult brain tumor. Recent evidence shows that GB cells form glutamatergic synapses with neurons, promoting tumor growth and invasion, yet the gene regulatory networks (GRNs) underlying this interaction remain underexplored. GRNs coordinate gene expression through interactions among transcription factors (TFs), enhancers, and promoters, and are often disrupted in cancer due to epigenetic and chromatin architecture changes. To identify GRNs involved in GB pathogenesis, we applied the machine learning-based MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) pipeline to integrate multi-omics data. GABA-signalling emerged as a previously unrecognized contributor to GB, involving relevant TFs as ARX, GSX2 and DLX family, key regulators of GABAergic interneuron development. Co-culture assays further demonstrated that GABAergic input promotes GB proliferation through non-synaptic mechanisms likely involving metabolic or paracrine interactions. Our findings reveal novel GRNs in GB, positioning GABA signalling as a potential therapeutic target to disrupt neuron-glioma interactions. SignificanceThis study uncovers novel gene regulatory networks driving glioblastoma progression through integration of multi-omics data with machine-learning tools. By identifying GABAergic signalling as a previously unrecognized contributor to tumour growth, it reveals new transcriptional regulators, providing valuable insights into neuron-glioma interactions. These findings open new therapeutic avenues for brain-cancer treatment. GRAPHICAL ABSTRAC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/651564v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@ed95e1org.highwire.dtl.DTLVardef@b1d9forg.highwire.dtl.DTLVardef@1c5bc00org.highwire.dtl.DTLVardef@b9d833_HPS_FORMAT_FIGEXP M_FIG C_FIG Integration of multi-omics data from glioblastoma (GB) patients identified networks related to GABA signalling as relevant for GB pathogenesis. In co-culture assays, GABAergic interneurons increase the proliferation of GB cells.