Modeling Medulloblastoma in Vivo and with Human Cerebellar Organoids

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jan 31

PMID 31996670

Citations 79

Authors

Claudio Ballabio

Marica Anderle

Matteo Gianesello

Chiara Lago

Evelina Miele

Marina Cardano

Giuseppe Aiello

Silvano Piazza

Davide Caron

Francesca Gianno

Andrea Ciolfi

Lucia Pedace

Angela Mastronuzzi

Marco Tartaglia

Franco Locatelli

Elisabetta Ferretti

Felice Giangaspero

Luca Tiberi

Affiliations

Soon will be listed here.

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.

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