Using known drivers of disease (PTCH1 and MYCN), we demonstrate robust generation of SHH-subtype medulloblastoma and cooperativity between heterozygosity for PTCH1 with mutations in DDX3X or GSE1. Thus, human NES cell-based models offer a powerful system for refined analyses of human medulloblastoma tumorigenesis, with the prospect of future applications in screening candidate therapeutic compounds. Here, PTCH1 is linked to medulloblastoma.