Genetically engineered cerebral organoids model brain tumour formation

Brain tumours 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 modelling human disease. Here, we establish a 3D in vitro model, named 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 define mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumour (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable to study aspects of tumour biology such as invasiveness, and to evaluate the effect of drugs in the context of specific DNA aberrations. neoCORs will provide a valuable complement to current basic and preclinical models for studying brain tumour biology.