Disrupting Gene Regulatory Networks in Glioblastoma to block Neuron-to-Glioma Synaptic communication.

Neuron-to-glioma synapses (i.e true synapses between neurons and brain tumour cells) drive tumour progression and invasion in glioblastoma (GB), the most aggressive primary brain tumour.

Our previous research uncovered profound epigenetic and 3D genomic alterations in GB, leading to changes in gene expression underlying such synaptic communication. Moreover, we identified the major gene regulatory networks (GRNs) and transcription factors (TFs, i.e. PITX1, SMAD3) mediating this process.

Here, we aim to develop strategies to disrupt these malignant GRNs in order to block neuron-to-glioma synapses, with the goal to ameliorate GB aggressiveness. For this purpose, we will take advantage of our expertise in GRNs, enhancer function and 3D genome organisation in GB.

We will apply a combination of cutting-edge techniques, including omics approaches to interrogate the 3D genome, the epigenome, and chromatin accessibility; scRNA-seq and scATAC-seq to study cell plasticity in response to neuronal activity; targeted protein degradation methods (TPD, e.g. PROTACS) to target TFs; and in vivo GB mouse models to evaluate the translational potential of disrupting GRNs in GB.

This approach presents a novel strategy against GB aiming to disrupt GRNs mediating neuron-to-glioma synapses with the aim of mitigating the aggressiveness of such a difficult-to-treat cancer as glioblastoma.