Functional genomic screens to determine initiating and maintenance events in human medulloblastoma (360G-Wellcome-201511_Z_16_Z)

Medulloblastoma (MB) is the most common malignant brain tumour in children. Four molecular subgroups have been identified through large-scale genomic studies, and approximately one-third of patients have the sonic hedgehog (SHH) subtype. Mutations in the SHH-receptor Patched (PTCH) are found in 25% of this sub-type. Mouse models have provided critical insight into mechanisms of MB initiation. However, the experimental tumours do not reflect the mutational complexity of the human disease. The co-operative events that initiate transformation of pre-malignant cells to MB in humans is unknown. Recent advances in stem cell technology have led to novel in vitro systems representing hindbrain precursors. Stable, long-term neuro-epithelial stem (NES) cells with hindbrain identity and potency for cerebellar cells have been generated during my time in Austin Smith’s lab from human pluripotent stem cells and directly from the human hindbrain. These cells represent a candidate cell of origin for MB, and my preliminary studies in collaboration with William Weiss show that NES cells harbouring germ-line mutations in PTCH generate medulloblastoma in xenografts. My goal for this fellowship is to use PTCH+/- NES cells in combination with genome-editing tools to discover genes that co-operate with PTCH to initiate and maintain MB in the human context.