Medulloblastoma (MB) is a highly invasive pediatric tumor of the cerebellum. Despite a better cure rate due to multimodal treatments that associate chemotherapy, surgery and radiotherapy (RT), 20-30% of the children are incurable. Moreover, survivors suffer from important side effects. Transcriptomic analyses have defined 4 molecular subgroups of MB. Among them, the group 3 which represents 25% of the patients is the most problematic at the clinical level. This subgroup is metastatic and resistant to all the current therapies. The 20 to 30% of patients that die from a MB essentially display a group 3 MB. At the molecular level, this subgroup is poorly characterized although we recently showed that it is driven by an abnormal identity unrelated to the cerebellum (Garancher et al., Cancer cell 2018). Since RT is central in MB treatment and that group 3 MB frequently relapse, the aim of our project is to study the mechanism by which Group 3 MB escape to RT. To that end, we will use different in vitro and in vivo models, such as MB cell lines, human patient-derived medulloblastoma (PDX) and primary mouse cerebellar progenitors modified by transduction (oncogene expression or KD (sh-CRISPR) of tumor suppressors). We will study their response to RT both in vitro but, more importantly, in vivo following orthopically grafting into the cerebellum of mice by stereotaxis. First, a targeted approach will be performed to investigate of the activation of p53 pathway and its role since, surprisingly, Group 3 MB keeps an intact WT TP53 gene. An unbiased approach by RNAseq will be next also undertaken. Clonal selection will be also investigated by barcoding and single-cell RNAseq and an unbiased CRISPR screen will be performed to investigate the mechanism of resistance.