A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories [snRNA_10Xv3]

Atypical teratoid rhabdoid tumors (ATRTs), characterized by the loss of SMARCB1, are among the most lethal pediatric brain tumors. Three molecular subtypes have been identified, each defined by distinct molecular and clinical features. Still, no subtype-specific treatments are available, highlighting the need to understand their inter and intra-subtype heterogeneity. Here, we generated a single-nucleus transcriptome atlas of ATRTs, validated with single-cell ATAC-seq and spatial transcriptomics, to study subtype-specific differentiation trajectories. We identified retained brain progenitor expression profiles within unique subtype-specific differentiation lineages. A shared cycling, progenitor-like cell population, interspersed throughout tumors, was observed across all ATRT patients. Finally, we demonstrate that subtype-specific differentiation trajectories can be induced pharmacologically in ATRT tumoroids directing tumor cells towards a non-proliferative, mature phenotype. Our study reveals that ATRT subtypes exhibit signaling trajectories mirroring normal fetal brain development, potentially enabling the development of maturation therapies tailored towards ATRTs.