Abstract
ABSTRACTSomatic 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.
Highlights
Disorders of brain growth are known to cause a wide range of physiological and pathological symptoms such as intractable epilepsy, intellectual disability, autism, cognitive and motor impairment (Aronica and Crino, 2014, Courchesne et al, 2001, Hevner, 2015)
Summary statement A new brain tumour model in zebrafish allows simultaneous analysis of malignant tumours and heterotopias, suggesting that both lesions originate from similar events, with Yap1 as a driving force in tumour development
We developed a zebrafish model of brain tumour based on somatic expression of oncogenes that activate MAPK/PI3K signalling in neural progenitor cells
Summary
Disorders of brain growth are known to cause a wide range of physiological and pathological symptoms such as intractable epilepsy, intellectual disability, autism, cognitive and motor impairment (Aronica and Crino, 2014, Courchesne et al, 2001, Hevner, 2015) Their causes are diverse and comprise: (i) focal lesions characterised by abnormal location of otherwise normally differentiated neural cells (Thom et al, 2004), (ii) “tuberous” formation and similar disorders with abnormally large neurons and/or other cell types (Blumcke et al, 2011, Crino, 2013) and (iii) brain overgrowth syndromes leading to diffuse megalencephaly or malformations (Winden et al, 2015), which are mostly limited to developmental stages. These pathways are altered in gliomas, as leading mutations in high grade gliomas include EGFR amplification (in 27-36 % of cases, (Ohgaki and Kleihues, 2007) or mutations (1831 % of cases, (Liu et al, 2005), deletion of PTEN, the inhibitor of AKT and mTOR
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