RESUMO
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.
Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transativadores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Aminoacil-tRNA Sintetases/genética , Animais , Neoplasias Encefálicas/genética , Carcinogênese/genética , Carcinogênese/patologia , Proliferação de Células , Sobrevivência Celular , Células Clonais , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Genes ras , Glioblastoma/genética , Glioblastoma/patologia , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Mesoderma/patologia , Células-Tronco Neurais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Telencéfalo/patologia , Proteínas de Sinalização YAP , Proteínas de Peixe-Zebra/genéticaRESUMO
Here we describe the conditional zebrafish cancer toolbox, which allows for fine control of the expression of oncogenes or downregulation of tumor suppressors at the spatial and temporal level. Methods such as the Gal4/UAS or the Cre/lox systems paved the way to the development of elegant tumor models, which are now being used to study cancer cell biology, clonal evolution, identification of cancer stem cells and anti-cancer drug screening. Combination of these tools, as well as novel developments such as the promising genome editing system through CRISPR/Cas9 and clever application of light reactive proteins will enable the development of even more sophisticated zebrafish cancer models. Here, we introduce this growing toolbox of conditional transgenic approaches, discuss its current application in zebrafish cancer models and provide an outlook on future perspectives.
