Journal Article

Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor–ligand interactions

Baumgartner, Alicia, Madlener, Sibylle, Slavc, Irene, Dorfer, Christian, Alencastro Veiga Cruzeiro, Gustavo, Baird, Lissa C., Lambo, Sander, Lötsch, Daniela, Freidel, Pia S., Schwalm, Benjamin, Tonn, Joerg C., Haase, Rebecca D., de Biagi, Carlos A. O., Thon, Niklas, Hack, Olivia A., Herms, Jochen, Korshunov, Andrey, Beck, Alexander, Mayr, Lisa, Englinger, Bernhard, Shaw, McKenzie L., Klenner, Marbod, Alexandrescu, Sanda, Yang, Edward, Pfister, Stefan M., Amberg, Nicole, Mack, Norman, Gojo, Johannes, Geyregger, Rene, Chi, Susan N., Filbin, Mariella G., Liu, Ilon, Nascimento Silva, Andrezza Do, Bruckner, Katharina, Senfter, Daniel, Kool, Marcel, Gabler-Pamer, Lisa, von Baumgarten, Louisa, Hovestadt, Volker, Haberler, Christine, Peyrl, Andreas

2025

Overview

Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor–ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies. Beck et al. conducted single-cell and spatial profiling of embryonal tumors with multilayered rosettes, finding that malignant cellular hierarchies are driven by developmental programs and specific members of the chromosome 19 microRNA cluster.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/1 / 13/89 / 14/32 / 38/23 / 38/91 / 45/23 / 631/136/142 / 631/337/384/331 / 631/67 / 692/4028/67/1678 / Age / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Brain - embryology / Brain - pathology / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Carcinogenesis / Cells / Child, Preschool / Chromosomes / Chromosomes, Human, Pair 19 / Datasets / DNA methylation / Genes / HEK293 Cells / Humans / Life Sciences / Ligands / Male / Medical prognosis / MicroRNAs / MicroRNAs - metabolism / Neoplasms, Germ Cell and Embryonal - drug therapy / Neoplasms, Germ Cell and Embryonal - genetics / Neoplasms, Germ Cell and Embryonal - metabolism / Neoplasms, Germ Cell and Embryonal - pathology / Neurogenesis / Patients / Pyrazoles / Quinoxalines / Signal Transduction / Single-Cell Gene Expression Analysis / Tumors / Visualization