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

Marie Mayrhofer (1) , Victor Gourain (1) , Markus Reischl (2) , Pierre Affaticati (3) , Armin Jenett (3) , Jean-Stéphane Joly (3) , Matteo Benelli (4) , Francesca Demichelis (4) , Pietro Luigi Poliani (5) , Dirk Sieger (6) , Marina Mione (4, 1)

1 ITG - Institute for Toxicology and Genetics
2 Institute for Applied Informatics
3 NeuroPSI - Institut des Neurosciences Paris-Saclay
4 UNITN - Università degli Studi di Trento = University of Trento
5 UniBs - Università degli Studi di Brescia = University of Brescia
6 Edin. - University of Edinburgh

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. HRAS(V12) 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 (YAP(S5A)) and HRAS(V12) 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.

Mots clés: Glioma; RAS; Zebrafish; Heterotopia

Mots clés: YAP

Domaines: Neurobiologie; Psychologie et comportements; Sciences cognitives

Marie Mayrhofer, Victor Gourain, Markus Reischl, Pierre Affaticati, Armin Jenett, et al.. A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth.. Disease Models & Mechanisms, 2017, 10 (1), pp.15-28. ⟨10.1242/dmm.026500⟩. ⟨hal-01420016⟩