SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors.

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we study derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids reveals a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently reveal patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 activates patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

Microglia in pediatric brain tumors: The missing link to successful immunotherapy.

Brain tumors are the leading cause of cancer-related mortality in children. Despite the development of immunotherapeutic strategies for adult brain tumors, progress in pediatric neuro-oncology has been hindered by the complex and poorly understood nature of the brain's immune system during early development, a phase that is critical for the onset of many pediatric brain tumors. A defining characteristic of these tumors is the abundance of microglia, the resident immune cells of the central nervous system. In this review, we explore the concept of microglial diversity across brain regions and throughout development and discuss how their maturation stage may contribute to tumor growth in children. We also summarize the current knowledge on the roles of microglia in common pediatric brain tumor entities and provide examples of myeloid-based immunotherapeutic strategies. Our review underscores the importance of microglial plasticity in pediatric brain tumors and its significance for developing effective immunotherapeutic strategies.