title: A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth.
abstract: Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12was 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 an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12abolishes 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 might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.
authors.affiliation: Institute for Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: Institute for Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Gourain
authors.affiliation: Institute for Applied Informatics at Karlsruhe Institute of Technology, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.affiliation: Tefor Core Facility, Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, Gif-sur-Ivette 91190, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Affaticati
authors.affiliation: Tefor Core Facility, Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, Gif-sur-Ivette 91190, France.
authors.forename: Arnim
authors.initials: A
authors.lastname: Jenett
authors.affiliation: Tefor Core Facility, Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, Gif-sur-Ivette 91190, France.
authors.forename: Jean-Stephane
authors.initials: JS
authors.lastname: Joly
authors.affiliation: Centre for Integrative Biology, University of Trento, Via Sommarive 9, Trento 38123, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.affiliation: Centre for Integrative Biology, University of Trento, Via Sommarive 9, Trento 38123, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia School of Medicine, Spedali Civili Brescia, Brescia 25123, Italy.
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Centre for Neuroregeneration, The University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
authors.forename: Dirk
authors.initials: D
authors.lastname: Sieger
authors.affiliation: Institute for Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany mariacaterina.mione@unitn.it.|Centre for Integrative Biology, University of Trento, Via Sommarive 9, Trento 38123, Italy.
authors.forename: Marina
authors.identifier: 0000-0002-9040-3705
authors.initials: M
authors.lastname: Mione
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D002999:Clone Cells; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013687:Telencephalon / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000604:Amino Acyl-tRNA Synthetases; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; D029961:Zebrafish Proteins; C583457:Yes-associated protein (yap), zebrafish; C527278:Zic4 protein, zebrafish
keywords: Glioma; Heterotopia; RAS; YAP; Zebrafish