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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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

摘要

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.