A Patient-specific screen identifies Medulloblastoma driver genes in-vivo and in human organoids. A Patient-specific screen identifies Medulloblastoma driver genes in-vivo and in human organoids

Group3 Medulloblastoma is a highly malignant pediatric brain tumor and despite patients harboring different genetic alterations they are treated with similar therapies. Here, we perform an in-vivo Patient-Specific screen and we identify Otx2 and c-Myc as strong inducers of Group3 Medulloblastoma. We demonstrate that the chromatin modifier Smarca4, also mutated in human patients, is able to reduce Otx2/c-Myc tumorigenic activity in-vivo. Furthermore, Otx2/c-Myc co-overexpression in human cerebellar organoids generates Medulloblastoma-like organoids that induce brain cancer in mice with a DNA methylation signature similar to human Group3 MB. Finally, inhibition of histone methyltransferases reduces Otx2/c-Myc tumorigenesis in ex-vivo culture and in human cerebellar organoids. Therefore, understanding the role of different altered genes in Medulloblastoma patients will be of great importance to develop new personalized therapies. Overall design: To classify new Group3 Medulloblastoma (MB) derived from human organoids, we analyzed the global DNA methylation profile of Otx2+c-Myc (OM) injected organoids and compared them with those derived from 36 MB patients, diagnosed and treated at the Ospedale Pediatrico Bambino Gesù (OPBG Rome).