Grant: Project Grant

Medulloblastoma is an aggressive brain cancer that most often affects children and adolescents. Current multimodal treatment comprising chemotherapy, surgery and radiation cures about ~70% of the patients. Neurosurgeons remove the tumor in the brain - the so called 'primary tumor' - very easily, however in some patients the tumor can spread (metastasize) to form cancer in other areas of the brain different from the original location. Very often these metastases present in the form of a layer of tumor cells that covers regions of the brain hardly accessible by surgery. As a consequence, medulloblastoma metastases are usually inoperable and patients that have metastases have a very low chance of survival. The therapies that work on the primary tumors are ineffective on the metastases for unknown reasons. In fact, despite metastases represent a major clinical challenge, almost no effort has been directed toward understanding the mechanisms of metastatic spread of medulloblastoma tumor cells. In this proposal we will use a new model of medulloblastoma metastasis based on human cells grown in mice. This approach will allow us to reproduce the life cycle of medulloblastoma in a mouse model, by the way of treating the tumor bearing mice with surgery, radiotherapy and chemotherapy with the same protocols used in paediatric medulloblastoma patients. Some medulloblastomas will metastasize, just like human cancers do, and then we will be able to directly compare the genetic mutations of the primary tumors and the metastases by using next-generation sequencing techniques. By direct comparison of pre-therapy and post-therapy metastases we will gain key knowledge into the mechanism of metastatic dissemination of medulloblastoma, and identify new potential targets for treatment.