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Dis Model Mech. 2017 Jan 1;10(1):15-28. doi: 10.1242/dmm.026500. Epub 2016 Nov 24.

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

Author information

1
Institute for Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany.
2
Institute for Applied Informatics at Karlsruhe Institute of Technology, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany.
3
Tefor Core Facility, Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, Gif-sur-Ivette 91190, France.
4
Centre for Integrative Biology, University of Trento, Via Sommarive 9, Trento 38123, Italy.
5
Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia School of Medicine, Spedali Civili Brescia, Brescia 25123, Italy.
6
Centre for Neuroregeneration, The University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
7
Institute for Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany mariacaterina.mione@unitn.it.

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.

KEYWORDS:

Glioma; Heterotopia; RAS; YAP; Zebrafish

PMID:
27935819
PMCID:
PMC5278524
DOI:
10.1242/dmm.026500
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing or financial interests.

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