Autonomous rhythmic activity in glioma networks drives brain tumour growth
Diffuse gliomas, particularly glioblastomas, are incurable brain tumours1. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients2-6. However, the networks’ architecture and communication strategy and how these influence tumour biology remain unk...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2023
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| In: |
Nature
Year: 2023, Volume: 613, Issue: 7942, Pages: 179-186 |
| ISSN: | 1476-4687 |
| DOI: | 10.1038/s41586-022-05520-4 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41586-022-05520-4 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41586-022-05520-4 
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| Author Notes: | David Hausmann, Dirk C. Hoffmann, Varun Venkataramani, Erik Jung, Sandra Horschitz, Svenja K. Tetzlaff, Ammar Jabali, Ling Hai, Tobias Kessler, Daniel D. Azoŕin, Sophie Weil, Alexandros Kourtesakis, Philipp Sievers, Antje Habel, Michael O. Breckwoldt, Matthia A. Karreman, Miriam Ratliff, Julia M. Messmer, Yvonne Yang, Ekin Reyhan, Susann Wendler, Cathrin Löb, Chanté Mayer, Katherine Figarella, Matthias Osswald, Gergely Solecki, Felix Sahm, Olga Garaschuk, Thomas Kuner, Philipp Koch, Matthias Schlesner, Wolfgang Wick, Frank Winkler |
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| 245 | 1 | 0 | |a Autonomous rhythmic activity in glioma networks drives brain tumour growth |c David Hausmann, Dirk C. Hoffmann, Varun Venkataramani, Erik Jung, Sandra Horschitz, Svenja K. Tetzlaff, Ammar Jabali, Ling Hai, Tobias Kessler, Daniel D. Azoŕin, Sophie Weil, Alexandros Kourtesakis, Philipp Sievers, Antje Habel, Michael O. Breckwoldt, Matthia A. Karreman, Miriam Ratliff, Julia M. Messmer, Yvonne Yang, Ekin Reyhan, Susann Wendler, Cathrin Löb, Chanté Mayer, Katherine Figarella, Matthias Osswald, Gergely Solecki, Felix Sahm, Olga Garaschuk, Thomas Kuner, Philipp Koch, Matthias Schlesner, Wolfgang Wick, Frank Winkler |
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| 520 | |a Diffuse gliomas, particularly glioblastomas, are incurable brain tumours1. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients2-6. 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 Ca2+ oscillations and are particularly connected to others. Their autonomous periodic Ca2+ transients preceded Ca2+ 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 Ca2+ activity generates a vulnerability7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs. | ||
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