Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing.

Cell 2025

Tetzlaff SK, Reyhan E, Layer N, Bengtson CP, Heuer A, Schroers J, Faymonville AJ, Langeroudi AP, Drewa N, Keifert E, Wagner J, Soyka SJ, Schubert MC, Sivapalan N, Pramatarov RL, Buchert V, Wageringel T, Grabis E, Wißmann N, Alhalabi OT, Botz M, Bojcevski J, Campos J, Boztepe B, Scheck JG, Conic SH, Puschhof MC, Villa G, Drexler R, Zghaibeh Y

Abstract

Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.

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