非典型畸胎瘤/横纹肌母细胞瘤（ATRT）是一种罕见但具有侵袭性的儿童脑肿瘤实体，其特征是基因上的SWI/SNF染色质重塑复合物成员SMARCB1 或SMARCA4的改变。ATRT可以根据其表观遗传特征进行进一步分类为不同的分子亚群。虽然最近的研究表明不同的亚群具有不同的临床特征，但迄今为止尚未开发出特定于亚群的治疗方案。这是由于缺乏代表不同分子亚群的临床前体外模型所导致的。在这里，我们描述了ATRT-MYC和ATRT-SHH亚群的ATRT瘤体模型的建立。我们证明ATRT瘤体保留了亚群特异性的表观遗传和基因表达特征。在我们的ATRT瘤体上进行高通量药物筛选揭示了ATRT-MYC和ATRT-SHH亚群之间以及内部明显的药物敏感性差异。虽然ATRT-MYC普遍对多靶向酪氨酸激酶抑制剂具有高度敏感性，但ATRT-SHH表现出更多样化的反应，其中一部分对NOTCH抑制剂具有高敏感性，这与NOTCH受体的高表达相对应。我们的ATRT瘤体是第一个代表儿童脑肿瘤器官细胞模型，为开发亚群特异性治疗方案提供了代表性的临床前模型。© 2023年。作者（们）。

Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to NOTCH inhibitors, which corresponded to high expression of NOTCH receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.© 2023. The Author(s).