Brain tumour cells interconnect to a functional and resistant network

• Published in: Nature (London) Vol. 528; no. 7580; pp. 93 - 98
• Main Authors: Osswald, Matthias, Jung, Erik, Sahm, Felix, Solecki, Gergely, Venkataramani, Varun, Blaes, Jonas, Weil, Sophie, Horstmann, Heinz, Wiestler, Benedikt, Syed, Mustafa, Huang, Lulu, Ratliff, Miriam, Karimian Jazi, Kianush, Kurz, Felix T., Schmenger, Torsten, Lemke, Dieter, Gömmel, Miriam, Pauli, Martin, Liao, Yunxiang, Häring, Peter, Pusch, Stefan, Herl, Verena, Steinhäuser, Christian, Krunic, Damir, Jarahian, Mostafa, Miletic, Hrvoje, Berghoff, Anna S., Griesbeck, Oliver, Kalamakis, Georgios, Garaschuk, Olga, Preusser, Matthias, Weiss, Samuel, Liu, Haikun, Heiland, Sabine, Platten, Michael, Huber, Peter E., Kuner, Thomas, von Deimling, Andreas, Wick, Wolfgang, Winkler, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.12.2015; Nature Publishing Group
• Subjects: 14/69; 631/67/1922; 631/67/2321; Animals; Astrocytoma - metabolism; Astrocytoma - pathology; Astrocytoma - radiotherapy; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Brain tumors; Cancer; Care and treatment; Cell Communication - radiation effects; Cell Death - radiation effects; Cell division; Cell Proliferation - radiation effects; Cell Surface Extensions - metabolism; Cell Surface Extensions - radiation effects; Cell Survival - radiation effects; Chemotherapy; Complications and side effects; Connexin 43 - metabolism; Disease Progression; Gap Junctions - metabolism; Gap Junctions - radiation effects; GAP-43 Protein - metabolism; Glioma - metabolism; Glioma - pathology; Glioma - radiotherapy; Health aspects; Humanities and Social Sciences; Humans; Male; Mice; Mice, Nude; Microscopy; multidisciplinary; Neoplasm Invasiveness; Proteins; Radiation Tolerance - drug effects; Rodents; Science; Tumors; Germany
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature16071

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease. Brain tumours are difficult to treat because of their propensity to infiltrate brain tissue; here long processes, or tumour microtubes, extended by astrocytomas are shown to promote brain infiltration and to create an interconnected network that enables multicellular communication and that protects the tumours from radiotherapy-induced cell death, suggesting that disruption of the network could be a new therapeutic approach. Microtube network protects tumours from therapeutics One of the factors making astrocyte-derived brain tumors difficult to treat is their tendency to infiltrate brain tissue. Frank Winkler and colleagues show that the long processes, or tumour microtubes, extended by astrocytomas promote brain infiltration and create an interconnected network that enables multicellular communication and protects the tumours from radiotherapy-induced cell death. The neuronal growth-associated protein 43 is identified as an important factor in this process. Disruption of the network of astrocytoma cell by targeting their tumour microtubes could be a new therapeutic approach.