Cellular hierarchies of ETMR are shaped by oncogenic miRNAs and receptor-ligand interactions

Embryonal tumor with multilayered rosettes (ETMR) is a malignant pediatric brain tumor with a dismal prognosis. The proposed oncogenic driver is amplification and fusion of the chromosome 19 miRNA cluster (C19MC). However, the ramifications of this distinct genetic event as well as the complex tumor architecture and the interactions between malignant cell types in ETMR remain vastly understudied. Here, we have analyzed a cohort of 11 ETMR patients using single-cell transcriptomic and multiplexed spatial protein profiling. We reveal a common, spatially distinct cellular hierarchy, closely resembling normal development presenting as a highly proliferative neural stem cell-like population that gives rise to neuron-like cells. C19MC, which is predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, indicated by high-resolution miRNA:mRNA analyses. Further, we show that FGF- and NOTCH-signaling, important for cell-cell interactions in ETMR, can be successfully targeted in preclinical ETMR models and ETMR patients. Taken together, our study provides unprecedented new insights into fundamental ETMR biology and a powerful rationale for more effective targeted therapies.