CNSC-11. INVESTIGATION OF GLIOBLASTOMA NEURON-TUMOR NETWORKS WITH RABIES-BASED RETROGRADE TRACING

Abstract Glioblastomas are primary brain tumors known for their whole-brain invasion and high therapeutic resistance. In previous studies, neuron-to-glioma synapses have been shown to promote glioblastoma progression. A deep characterization of this communication and of tumor-connected neurons has not been possible due to technological limitations. We adapted a rabies virus-based retrograde tracing approach to investigate and manipulate neuron-tumor networks. Interestingly, we found that glioblastoma cells rapidly integrated into neural circuits across the brain, engaging with distal neurons of diverse subtypes in very early stages of tumor development. Beyond glutamatergic neurons, we identified cholinergic neurons as drivers of glioblastoma cell invasion. We revealed patient- and tumor cell state-dependent differences in the expression of synaptogenic genes which also correlated with neuron-tumor connectivity and tumor cell invasivity. Notably, radiotherapy led to increased neuron-tumor connectivity mediated via neuronal hyperexcitability. The anti-epileptic drug perampanel alongside radiotherapy mitigated this effect and enhanced treatment efficacy by simultaneous neuronal activity inhibition. Utilizing our rabies-based approach, we genetically ablated tumor-connected neurons leading to a significantly decreased tumor progression offering a potential novel therapeutic avenue. Taken together, we developed a framework for dedicated analysis of multicellular neuron-tumor networks and propose our methodology as a versatile and adaptable approach to tackle glioblastoma.