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 and Luca Tiberi ()
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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
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
Elisabetta Ferretti: Sapienza University
Felice Giangaspero: University Sapienza of Rome
Luca Tiberi: University of Trento

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13989-3

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DOI: 10.1038/s41467-019-13989-3

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