Abstract
Atypical teratoid rhabdoid tumors (ATRT) are challenging pediatric brain tumors which are predominantly associated with inactivation of the gene SMARCB1. As SMARCB1 is a conserved subunit of the chromatin remodeling BAF complex, we hypothesize that the effect of its loss of function is influenced by the epigenetic landscape of the cell in which deletion occurs, resulting in constrained age of onset and tissue specificity of tumor formation. To address this question and identify potential interactions between SMARCB1 loss and the process of neural development, we generated a model of ATRT using an inducible SMARCB1 loss of function system in human induced pluripotent stem cells (iPSCs) which were used to form cerebral organoids. We have identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and have identified neural cell types which are particularly vulnerable to SMARCB1 loss. Our results suggest that SMARCB1 loss likely interacts with processes of neural development for ATRT tumorigenesis.