Modeling medulloblastoma in vivo and with human cerebellar organoids.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Ballabio C,Anderle M,Gianesello M,Lago C,Miele E,Cardano M,Aiello G,Piazza S,Caron D,Gianno F,Ciolfi A,Pedace L,Mastronuzzi A,Tartaglia M,Locatelli F,Ferretti E,Giangaspero F,Tiberi L

doi

10.1038/s41467-019-13989-3

subject

Has Abstract

pub_date

2020-01-29 00:00:00

pages

583

issue

1

issn

2041-1723

pii

10.1038/s41467-019-13989-3

journal_volume

11

pub_type

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