ZFIN ID: ZDB-PUB-161211-4
A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth
Mayrhofer, M., Gourain, V., Reischl, M., Affaticati, P., Jenett, A., Joly, J.S., Benelli, M., Demichelis, F., Poliani, P.L., Sieger, D., Mione, M.
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
Microarrays: GEO:GSE74754
MeSH Terms:
  • Amino Acyl-tRNA Synthetases/genetics
  • Animals
  • Brain Neoplasms/enzymology*
  • Brain Neoplasms/genetics
  • Brain Neoplasms/pathology*
  • Carcinogenesis/genetics
  • Carcinogenesis/pathology
  • Cell Proliferation
  • Cell Survival
  • Clone Cells
  • Disease Models, Animal
  • Enhancer Elements, Genetic/genetics
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Glioblastoma/genetics
  • Glioblastoma/pathology
  • Green Fluorescent Proteins/metabolism
  • Humans
  • Immunohistochemistry
  • Mesoderm/pathology
  • Mitogen-Activated Protein Kinases/metabolism*
  • Neural Stem Cells/metabolism
  • Phosphatidylinositol 3-Kinases/metabolism*
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Signal Transduction
  • Telencephalon/pathology
  • Trans-Activators/metabolism*
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 27935819 Full text @ Dis. Model. Mech.
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.