Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.

Modeling medulloblastoma in vivo and with human cerebellar organoids / Ballabio, Claudio; Anderle, Marica; Gianesello, Matteo; Lago, Chiara; Miele, Evelina; Cardano, Marina; Aiello, Giuseppe; Piazza, Silvano; Caron, Davide; Gianno, Francesca; Ciolfi, Andrea; Pedace, Luca; Mastronuzzi, Angela; Tartaglia, Marco; Locatelli, Franco; Ferretti, Elisabetta; Giangaspero, Felice; Tiberi, Luca. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020). [10.1038/s41467-019-13989-3]

Modeling medulloblastoma in vivo and with human cerebellar organoids

Miele Evelina;Gianno Francesca;Ciolfi Andrea;Mastronuzzi Angela;Locatelli Franco;Ferretti Elisabetta;Giangaspero Felice
Penultimo
;
2020

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.
2020
benzamides; brain neoplasms; carcinogenesis; cell line; tumor; cerebellar neoplasms; DNA helicases; DNA methylation; enhancer of zeste homolog 2 protein; gene expression regulation; neoplastic; humans; medulloblastoma; nuclear proteins; organoids; otx transcription factors; proto-oncogene proteins c-myc; pyridones; stem cells; transcription factors
01 Pubblicazione su rivista::01a Articolo in rivista
Modeling medulloblastoma in vivo and with human cerebellar organoids / Ballabio, Claudio; Anderle, Marica; Gianesello, Matteo; Lago, Chiara; Miele, Evelina; Cardano, Marina; Aiello, Giuseppe; Piazza, Silvano; Caron, Davide; Gianno, Francesca; Ciolfi, Andrea; Pedace, Luca; Mastronuzzi, Angela; Tartaglia, Marco; Locatelli, Franco; Ferretti, Elisabetta; Giangaspero, Felice; Tiberi, Luca. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020). [10.1038/s41467-019-13989-3]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1414685
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