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

Autor:	Tetzlaff SK; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Reyhan E; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Layer N; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Bengtson CP; Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany., Heuer A; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Schroers J; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Faymonville AJ; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Langeroudi AP; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Drewa N; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Keifert E; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Wagner J; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Soyka SJ; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Schubert MC; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Sivapalan N; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Pramatarov RL; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Buchert V; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Wageringel T; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany., Grabis E; Translational Neurosurgery, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Wißmann N; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Alhalabi OT; Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany., Botz M; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Bojcevski J; Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Campos J; Chica and Heinz Schaller Foundation, Institute of Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Boztepe B; Neuroradiology Department, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Scheck JG; Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Neuroradiology Department, University Hospital Heidelberg, Heidelberg, Germany., Conic SH; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany., Puschhof MC; Faculty of Medicine, Heidelberg University, and Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg, Germany., Villa G; Translational Neurosurgery, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany., Drexler R; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA., Zghaibeh Y; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Hausmann F; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Hänzelmann S; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Karreman MA; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Kurz FT; Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Neuroradiology, University Hospital Geneva, Geneva, Switzerland., Schröter M; ETH Zurich, Department of Biosystems Science and Engineering, Basel, Switzerland., Thier M; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany., Suwala AK; Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology (B300), German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Forsberg-Nilsson K; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden., Acuna C; Chica and Heinz Schaller Foundation, Institute of Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Saez-Rodriguez J; Faculty of Medicine, Heidelberg University, and Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg, Germany., Abdollahi A; Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Sahm F; Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology (B300), German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Breckwoldt MO; Neuroradiology Department, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Suchorska B; Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany., Ricklefs FL; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Heiland DH; Translational Neurosurgery, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany., Venkataramani V; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany. Electronic address: varun.venkataramani@med.uni-heidelberg.de.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Dec 03. Date of Electronic Publication: 2024 Dec 03.
DOI:	10.1016/j.cell.2024.11.002
Abstrakt:	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. Competing Interests: Declaration of interests J.S.-R. reports funding from GSK, Pfizer, and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer, and Grunenthal. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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