Complexity in Simplicity: Unraveling the Heterogeneous Nature of Malignant Rhabdoid Tumors

In this thesis we study the heterogeneity seen within the childhood cancer: malignant rhabdoid tumors (MRTs). These tumores are defined solely by loss of SMARCB1, a gene which is part of the swi/snf complex. Although we can only identify this one single genetic driver event, several subgroups can be identified based on DNA methylation profiling as well as molecular characteristics. In the body they can occur either outside of the brain (extra-cranial MRTs) or in the brain called atypical teratoid rhabdoid tumors (ATRTs), which are subdivided into the subgroups MYC, SHH and TYR. In this thesis we investigated the differences between these subgroups on different levels. Firstly, we set out to establish new patient-derived organoid models from the ATRT-MYC and ATRT-SHH group and identified new subgroup-specific drug compounds via high throughput drug screens. Secondly, we looked into the different ways of how ecMRTs are genetically regulated and studied their chromatin organization finding patient-specific enhancer-promoter loops activating the MYC oncogene. And lastly, we studied the intertumoral differences on single cell RNA and ATAC level of the different ATRT subgroups.