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Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing

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 rabie...

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Main Authors: Tetzlaff, Svenja (Author) , Reyhan, Ekin (Author) , Layer, Nikolas (Author) , Bengtson, C. Peter (Author) , Heuer, Alina (Author) , Schroers, Julian (Author) , Faymonville, Anton J. (Author) , Langeroudi, Atefeh Pourkhalili (Author) , Drewa, Nina (Author) , Keifert, Elijah (Author) , Wagner, Julia (Author) , Soyka, Stella (Author) , Schubert, Marc Cicero (Author) , Sivapalan, Nirosan (Author) , Pramatarov, Rangel (Author) , Buchert, Verena (Author) , Wageringel, Tim (Author) , Grabis, Elena (Author) , Wißmann, Niklas (Author) , Alhalabi, Obada (Author) , Botz, Michael (Author) , Bojcevski, Jovana (Author) , Campos, Joaquín (Author) , Boztepe, Berin (Author) , Scheck, Jonas (Author) , Conic, Sascha Henry (Author) , Puschhof, Maria C. (Author) , Villa, Giulia (Author) , Drexler, Richard (Author) , Zghaibeh, Yahya (Author) , Hausmann, Fabian (Author) , Hänzelmann, Sonja (Author) , Karreman, Matthia A. (Author) , Kurz, Felix T. (Author) , Schröter, Manuel (Author) , Thier, Marc Christian (Author) , Suwala, Abigail Kora (Author) , Forsberg-Nilsson, Karin (Author) , Acuna Goycolea, Claudio (Author) , Sáez Rodríguez, Julio (Author) , Abdollahi, Amir (Author) , Sahm, Felix (Author) , Breckwoldt, Michael O. (Author) , Suchorska, Bogdana (Author) , Ricklefs, Franz Lennard (Author) , Heiland, Dieter Henrik (Author) , Venkataramani, Varun (Author)
Format: Article (Journal)
Language:English
Published: January 23, 2025
In: Cell
Year: 2025, Volume: 188, Issue: 2, Pages: 390-411.e36
ISSN:1097-4172
DOI:10.1016/j.cell.2024.11.002
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.cell.2024.11.002
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0092867424012765
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Author Notes:Svenja K. Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J. Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J. Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel L. Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T. Alhalabi, Michael Botz, Jovana Bojcevski, Joaquín Campos, Berin Boztepe, Jonas G. Scheck, Sascha Henry 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 Saez-Rodriguez, Amir Abdollahi, Felix Sahm, Michael O. Breckwoldt, Bogdana Suchorska, Franz L. Ricklefs, Dieter Henrik Heiland, and Varun Venkataramani
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Summary: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.
Item Description:Gesehen am 23.10.2025
Physical Description:Online Resource
ISSN:1097-4172
DOI:10.1016/j.cell.2024.11.002

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