Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models. Three-dimensional organoid culture models offer innovative possibilities for the modeling of human disease. Here we establish a 3D in vitro model called a neoplastic cerebral organoid (neoCOR), in which we recapitulate brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR-Cas9-mediated mutagenesis. By screening clinically relevant mutations identified in cancer genome projects, we defined mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumor (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable for use in investigations of aspects of tumor biology such as invasiveness, and for evaluation of drug effects in the context of specific DNA aberrations. NeoCORs will provide a valuable complement to the current basic and preclinical models used to study brain tumor biology.

中文翻译：

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基因工程大脑类器官模拟脑肿瘤形成。

脑肿瘤是最致命和最具破坏性的癌症之一。他们的研究受到遗传异质性和可用实验室模型不完整的限制。三维类器官培养模型为人类疾病建模提供了创新的可能性。在这里，我们建立了一个称为肿瘤性脑类器官 (neoCOR) 的 3D 体外模型，在该模型中，我们通过转座子和 CRISPR-Cas9 介导的诱变在脑类器官中引入致癌突变来概括脑肿瘤发生。通过筛选癌症基因组项目中发现的临床相关突变，我们定义了导致胶质母细胞瘤样和中枢神经系统原始神经外胚层肿瘤 (CNS-PNET) 样肿瘤的突变组合。我们证明，neoCORs 适用于研究肿瘤生物学的各个方面，例如侵袭性，以及在特定 DNA 畸变的情况下评估药物效果。NeoCORs 将为当前用于研究脑肿瘤生物学的基础和临床前模型提供有价值的补充。