Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
Department of Pediatric Hematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Nat Commun. 2020 Jan 29;11(1):583. doi: 10.1038/s41467-019-13989-3.
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.
髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤，在亚型中，第 3 组 MB 的预后最差。在这里，我们进行了一项体内、患者特异性的筛选，从而鉴定出 Otx2 和 c-MYC 是第 3 组 MB 的强诱导剂。我们在人类小脑类器官中验证了我们的发现，其中 Otx2/c-MYC 产生具有与人类第 3 组肿瘤聚类的 DNA 甲基化特征的 MB 样类器官。此外，我们表明 SMARCA4 能够减少体内和人类小脑类器官中 Otx2/c-MYC 的致瘤活性，而在人类 MB 患者中发现的突变形式 SMARCA4 T910M 抑制野生型蛋白功能。最后，用 EZH2 特异性抑制剂 Tazemetostat 处理可减少体外培养和人类小脑类器官中 Otx2/c-MYC 的致瘤性。总之，人类小脑类器官可有效地用于了解在癌症患者中发现的基因的作用，并代表开发个性化治疗方法的可靠工具。
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