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Modeling medulloblastoma in vivo and with human cerebellar organoids

Author

Listed:
  • Claudio Ballabio

    (University of Trento)

  • Marica Anderle

    (University of Trento)

  • Matteo Gianesello

    (University of Trento)

  • Chiara Lago

    (University of Trento)

  • Evelina Miele

    (Bambino Gesù Children’s Hospital, IRCCS)

  • Marina Cardano

    (University of Trento)

  • Giuseppe Aiello

    (University of Trento)

  • Silvano Piazza

    (University of Trento)

  • Davide Caron

    (University of Trento)

  • Francesca Gianno

    (University Sapienza of Rome
    IRCCS Neuromed, Pozzilli)

  • Andrea Ciolfi

    (Ospedale Pediatrico Bambino Gesù, IRCCS)

  • Lucia Pedace

    (Bambino Gesù Children’s Hospital, IRCCS)

  • Angela Mastronuzzi

    (Bambino Gesù Children’s Hospital, IRCCS)

  • Marco Tartaglia

    (Ospedale Pediatrico Bambino Gesù, IRCCS)

  • Franco Locatelli

    (Bambino Gesù Children’s Hospital, IRCCS
    University of Rome)

  • Elisabetta Ferretti

    (Sapienza University)

  • Felice Giangaspero

    (University Sapienza of Rome
    IRCCS Neuromed, Pozzilli)

  • Luca Tiberi

    (University of Trento)

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.

Suggested Citation

  • Claudio Ballabio & Marica Anderle & Matteo Gianesello & Chiara Lago & Evelina Miele & Marina Cardano & Giuseppe Aiello & Silvano Piazza & Davide Caron & Francesca Gianno & Andrea Ciolfi & Lucia Pedace, 2020. "Modeling medulloblastoma in vivo and with human cerebellar organoids," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13989-3
    DOI: 10.1038/s41467-019-13989-3
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    Cited by:

    1. Francesco Antonica & Lucia Santomaso & Davide Pernici & Linda Petrucci & Giuseppe Aiello & Alessandro Cutarelli & Luciano Conti & Alessandro Romanel & Evelina Miele & Toma Tebaldi & Luca Tiberi, 2022. "A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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