Modeling medulloblastoma in vivo and with human cerebellar organoids

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

Research output: Contribution to journalArticlepeer-review

3 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)583
JournalNat. Commun.
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 29 2020

Keywords

  • Benzamides/antagonists & inhibitors
  • Brain Neoplasms/metabolism
  • Carcinogenesis
  • Cell Line, Tumor
  • Cerebellar Neoplasms/genetics
  • DNA Helicases/genetics
  • DNA Methylation
  • Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Medulloblastoma/genetics
  • Nuclear Proteins/genetics
  • Organoids/metabolism
  • Otx Transcription Factors/genetics
  • Proto-Oncogene Proteins c-myc/genetics
  • Pyridones/antagonists & inhibitors
  • Stem Cells
  • Transcription Factors/genetics

Fingerprint

Dive into the research topics of 'Modeling medulloblastoma in vivo and with human cerebellar organoids'. Together they form a unique fingerprint.

Cite this