ORIGIN4MB · Uncovering the cell of origin of Group 4 Medulloblastoma

Medulloblastoma (MB) is the most common malignant paediatric brain tumour, affecting mostly infants and children, and to a lesser extent adults. It originates from neuronal stem or progenitor cell populations on the cerebellum or brainstem during development and/or childhood, comprising around 60% of childhood intracranial embryonal tumours. The main risk factors associated with this condition are heritable factors, including germline mutations in genes that regulate developmental signaling pathways in the cerebellum. MB are classified in 4 subgroups (Wnt, Sonic Hedgeghog (SHH), Group 3 and Group 4) according to their gene expression, cell of origin, methylation patterns and clinical features. Group 4 MB is the most common subgroup of MB, affecting approximately 40% of the patients with this condition. The cellular origins of Group 4 MB are still under debate; however, recent papers using single cell RNA sequencing showed that Group 4 MBs are characterized by the expression of transcription factors such as Eomesodermin(EOMES) and LIM/Homeobox protein 2(LHX2) genes expressed by granule upper rhombic lip progenitors, more specifically Unipolar Brush Cells(UBCs) that are born during cerebellar morphogenesis. Therefore, one can hypothesize that Group 4 MB originates from UBCs progenitors. The main goals of the ORIGIN4MB project are to uncover the cell of origin of Group 4 MB and to develop the first pre-clinical model of Group 4 MB, revealing unprecendented insights in MB biology. To this end we will use lineage tracing techniques, lentiviral in utero infection, in vivo imaging and post-mortem analysis. We will also validate if the generated mouse model is able to recapitulate the human disease. This validation will determine if this model could be used to develop new treatments for Group 4 MB, opening the door to new therapeutic avenues for those pedeatric patients, ultimately improving their quality of life.