Autonomous rhythmic activity in glioma networks drives brain tumour growth.

Autor: Hausmann D; 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., Hoffmann DC; 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., 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., Jung 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., Horschitz S; Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany., Tetzlaff SK; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Jabali A; Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany., Hai L; 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.; Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Kessler T; 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., Azoŕin DD; 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., Weil S; 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., Kourtesakis A; 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., Sievers P; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Habel A; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Breckwoldt MO; Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany., Karreman MA; 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., Ratliff M; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany., Messmer JM; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Yang Y; 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., 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., Wendler S; 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., Löb C; 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., Mayer C; 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., Figarella K; Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany., Osswald M; 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., Solecki G; 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.; Business Unit Service and Customer Care, Carl Zeiss Microscopy, Jena, Germany., Sahm F; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Garaschuk O; Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany., Kuner T; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany., Koch P; Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany., Schlesner M; Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany., Wick W; 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., Winkler F; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. frank.winkler@med.uni-heidelberg.de.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. frank.winkler@med.uni-heidelberg.de.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Jan; Vol. 613 (7942), pp. 179-186. Date of Electronic Publication: 2022 Dec 14.
DOI: 10.1038/s41586-022-05520-4
Abstrakt: Diffuse gliomas, particularly glioblastomas, are incurable brain tumours 1 . They are characterized by networks of interconnected brain tumour cells that communicate via Ca 2+ transients 2-6 . However, the networks' architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca 2+ oscillations and are particularly connected to others. Their autonomous periodic Ca 2+ transients preceded Ca 2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca 2+ activity generates a vulnerability 7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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