Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing

Medulloblastoma (MB) is one of the most common malignant brain tumor in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development; however, they may not be suitable for high-throughput screening efforts. We demonstrate here that transplantation of ten different MB cell lines or patient-derived cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing.