Development, relapse and treatment of malignant pediatric brain tumors

Despite intensive research, better surgery and more precise radiotherapy, cancer and in particular brain tumors is still the main cause of death in children under 15. Medulloblastoma (MB) is the most common malignant brain tumor in children with about 70% overall survival.

This proposal aims to resolve where brain tumors driven by the MYC cancer gene are arising and how they become therapy resistant.First we will study our novel MYC-driven mouse model with lineage tracing and singel cell analysis to confirm if cells of tumor origin arise in the developing pineal gland.

We will compare the model to human MB but also to pineoblastoma, an equally agressive brain tumor.

Next, we will see if photosensitive (CRX+) cells in the two regions cerebellum and pineal gland can initiate brain tumors of the same entity or to two distinct ones.

With our inducbile CRX-driven model we can isolate photosensitive cells from both regions and study tumor initation with MYC lentiviruses but also generate a new model where MYC can be induced in rare CRX+ cerebellar cells.

We will see if MYC can also transform human cells into tumors and will then use iPS-derived stem cells that we differentiate into photosensitive cells.We will finally describe how therapy resistance is initiated and maintained using paired primary-relapse patient biopsies, barcoding and singel cell analysis.

This will give important clues for designing individuallized treatment options for patients affected by this fatal disease.