Medulloblastoma (MB) is a pediatric cancer with a developmental origin and arising from the cerebellum. Four MB molecular subgroups (WNT, Sonic Hedgehog (SHH), Group 3, Group 4) have been characterized with various clinical presentations and prognosis. Group 3 MB is the most aggressive and yet the least understood subgroup with still unclearly defined cells of origin. It affects mostly infants and children and has a high propensity to disseminate in the brain and in the leptomeningeal space.

The current animal models - xenografted or genetically engineered adult mice - do not allow to study the early steps of MB tumorigenesis and they occult the fact that this cancer develops in an immature organism. The aim of our study is to insert MB cells in their territory of origin, the developing cerebellum, and to characterize their early interactions with the embryonic microenvironment. The underlying questions are (i) whether MB cells have kept features from their cells of origin and (ii) if they are able to exploit the developmental signals to their advantage. We have set up the graft of fluorescent human MB cells in the cerebellum primordium of a chick embryo. Clearing and light-sheet imaging of the whole embryo allows the observation of a primary tumor and of leptomeningeal and ependymal metastatic invasion.

Once in their territory of origin, MB cells display neuronal features and a migratory behavior. These observations suggest that MB cells have indeed kept the ability to “read” the signals from the embryonic microenvironment. In the aim of characterizing this molecular dialogue we performed a transcriptomic analysis on the MB cells few days after graft. Slit/Robo signaling is one of the most significantly enriched pathways in the MB cells once grafted in the embryonic cerebellum. This pathway is of particular interest as it is involved in the early cerebellum development and appears to be deregulated in patients’ tumors. We are currently studying the way MB cells exploit this canonical pathway in an opportunistic manner.

Contact : karin.sadoul@univ-grenoble-alpes.fr