PUBLICATION

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

Authors
Mayrhofer, M., Gourain, V., Reischl, M., Affaticati, P., Jenett, A., Joly, J.S., Benelli, M., Demichelis, F., Poliani, P.L., Sieger, D., Mione, M.
ID
ZDB-PUB-161211-4
Date
2017
Source
Disease models & mechanisms   10(1): 15-28 (Journal)
Registered Authors
Gourain, Victor, Joly, Jean-Stephane, Mione, Marina, Sieger, Dirk
Keywords
Glioma, YAP, RAS, Zebrafish, Heterotopia
Datasets
GEO:GSE74754
MeSH Terms
  • Neural Stem Cells/metabolism
  • Cell Survival
  • Clone Cells
  • Disease Models, Animal
  • Mesoderm/pathology
  • Genes, ras
  • Gene Expression Regulation, Neoplastic
  • Mitogen-Activated Protein Kinases/metabolism*
  • Telencephalon/pathology
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Trans-Activators/metabolism*
  • Cell Proliferation
  • Phosphatidylinositol 3-Kinases/metabolism*
  • Green Fluorescent Proteins/metabolism
  • Zebrafish/metabolism*
  • Amino Acyl-tRNA Synthetases/genetics
  • Humans
  • Immunohistochemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Enzyme Activation
  • Enhancer Elements, Genetic/genetics
  • Brain Neoplasms/enzymology*
  • Brain Neoplasms/genetics
  • Brain Neoplasms/pathology*
  • Glioblastoma/genetics
  • Glioblastoma/pathology
  • Carcinogenesis/genetics
  • Carcinogenesis/pathology
  • Animals
  • Signal Transduction
(all 32)
PubMed
27935819 Full text @ Dis. Model. Mech.
CTD
27935819
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 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 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 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 might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
hzm5Et; io006TgcontrolProtruding-mouth
hzm5Et; io006TgcontrolDays 7-13 to Days 30-44
hzm5Et; io006TgcontrolAdult
1 - 3 of 3
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hzm5EtTransgenic Insertion
    io006TgTransgenic Insertion
      ka201TgTransgenic Insertion
        utn1TgTransgenic Insertion
          utn2TgTransgenic Insertion
            1 - 5 of 5
            Show
            Human Disease / Model
            Human Disease Fish Conditions Evidence
            brain cancerhzm5Et; io006TgcontrolTAS
            1 - 1 of 1
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            Sequence Targeting Reagents
            No data available
            Fish
            Fish
            hzm5Et
            hzm5Et; io006Tg
            1 - 2 of 2
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            Antibodies
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            BFPEFGBFP
            CFPEFGCFP
            EGFPEFGEGFP
            GAL4TA4EFGGAL4TA4
            GFPEFGGFP
            mCherryEFGmCherry
            1 - 6 of 6
            Show
            Mapping
            No data available
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            Citation
            Mayrhofer, M., Gourain, V., Reischl, M., Affaticati, P., Jenett, A., Joly, J.S., Benelli, M., Demichelis, F., Poliani, P.L., Sieger, D., Mione, M. (2017) A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth. Disease models & mechanisms. 10(1):15-28.