Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing
Svenja Kristin Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia A. Wagner, Stella J Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel Lyubomirov Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada Alhalabi, Michael Botz, Jovana Bojcevski, Joaquín Campos, Berin Boztepe, Jonas G. Scheck, Sascha Conic, Maria C. Puschhof, Giulia Villa, Richard Drexler, Yahya Zghaibeh, Fabian Hausmann, Sonja Hänzelmann, Matthia A. Karreman, Felix T. Kurz, Manuel Schröter, Marc Thier, Abigail K. Suwala, Karin Forsberg‐Nilsson, Claudio Acuna, Julio Sáez-Rodríguez, Amir Abdollahi, Felix Sahm, Michael O. Breckwoldt, Bogdana Suchorska, Franz Ricklefs, Dieter Henrik Heiland, Varun Venkataramani
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. • Rabies-based retrograde tracing maps brain-wide neuronal connectome of glioblastoma • Rapid neuronal integration of glioblastoma precedes neuronal dysfunction • Radiotherapy and perampanel show additive effects by disrupting neuron-tumor networks • Rabies-mediated genetic ablation of neurons halts glioblastoma progression Rapid integration of glioblastoma into neuronal circuits promotes glioblastoma invasion and growth, as shown by rabies-based retrograde tracing. Targeting of neuron-tumor networks with pharmacological or rabies-mediated disconnection offers therapeutic potential.