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A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth

Mayrhofer, Marie; Gourain, Victor; Reischl, Markus ORCID iD icon 1; Affaticati, Pierre; Jenett, Arnim; Joly, Jean-Stephane; Benelli, Matteo; Demichelis, Francesca; Poliani, Pietro Luigi; Sieger, Dirk; Mione, Marina
1 Karlsruher Institut für Technologie (KIT)

Abstract:

Somatic mutations activating MAPK/PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumour based on somatic expression of oncogenes that activate MAPK/PI3K signalling in neural progenitor cells. HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho‑(p)ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of a 8-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide TCGA sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP may be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours may originate from the same somatic mutations activating oncogenes and established that YAP activation is a hallmark of malignant brain tumours.


Verlagsausgabe §
DOI: 10.5445/IR/1000063263
Veröffentlicht am 15.03.2018
Originalveröffentlichung
DOI: 10.1242/dmm.026500
Scopus
Zitationen: 51
Web of Science
Zitationen: 50
Dimensions
Zitationen: 61
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Angewandte Informatik (IAI)
Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2017
Sprache Englisch
Identifikator ISSN: 1754-8403, 1754-8411
urn:nbn:de:swb:90-632633
KITopen-ID: 1000063263
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in Disease models & mechanisms
Verlag The Company of Biologists
Band 10
Seiten 15-28
Bemerkung zur Veröffentlichung 2016 online veröffentlicht
Vorab online veröffentlicht am 24.11.2016
Nachgewiesen in Web of Science
Dimensions
Scopus
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