Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor–ligand interactions
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.
Authors
- Mariella G. Filbin (ORCID: https://orcid.org/0000-0002-2613-8126)
- J. C. Tonn (ORCID: https://orcid.org/0009-0004-1756-423X)
- Sanda Alexandrescu (ORCID: https://orcid.org/0000-0001-9246-4184)
- Nicole Amberg (ORCID: https://orcid.org/0000-0002-3183-8207)
- Ilon Liu (ORCID: https://orcid.org/0000-0002-6186-3630)
- McKenzie Shaw (ORCID: https://orcid.org/0000-0003-3734-5312)
- Gustavo Alencastro Veiga Cruzeiro (ORCID: https://orcid.org/0000-0002-0005-3984)
- Irene Slavc (ORCID: https://orcid.org/0000-0002-9419-6790)
- Louisa von Baumgarten (ORCID: https://orcid.org/0000-0002-6634-0927)
- Edward Yang (ORCID: https://orcid.org/0000-0002-9912-4163)
- Sibylle Madlener (ORCID: https://orcid.org/0000-0001-7099-9997)
- Benjamin Schwalm
- Andrey Korshunov (ORCID: https://orcid.org/0000-0002-5257-3623)
- Johannes Gojo (ORCID: https://orcid.org/0000-0002-8113-3416)
- Alexander Beck (ORCID: https://orcid.org/0000-0001-8641-7832)
- Marbod Klenner
- Stefan M. Pfister (ORCID: https://orcid.org/0000-0002-5447-5322)
- Alicia Baumgartner (ORCID: https://orcid.org/0000-0002-0894-4167)
- Bernhard Englinger (ORCID: https://orcid.org/0000-0002-9701-2600)
- Katharina Bruckner (ORCID: https://orcid.org/0000-0002-6633-4009)
- Carlos Alberto Oliveira de Biagi (ORCID: https://orcid.org/0000-0003-0700-3135)
- Olivia A. Hack (ORCID: https://orcid.org/0000-0003-3962-1560)
- Christian Dorfer (ORCID: https://orcid.org/0000-0002-1843-7732)
- Sander Lambo (ORCID: https://orcid.org/0000-0002-2357-3114)
- Lissa Catherine Baird (ORCID: https://orcid.org/0000-0001-7996-1020)
- Susan Chi (ORCID: https://orcid.org/0000-0001-7753-878X)
- Jochen Herms (ORCID: https://orcid.org/0000-0002-6201-1042)
- Daniel Senfter (ORCID: https://orcid.org/0000-0001-9203-4563)
- Marcel Kool (ORCID: https://orcid.org/0000-0002-6557-5468)
- Volker Hovestadt (ORCID: https://orcid.org/0000-0002-3480-6649)
- Niklas Thon (ORCID: https://orcid.org/0000-0003-0011-5281)
- Christine Haberler (ORCID: https://orcid.org/0000-0003-1016-0545)
- Pia Freidel
- Andreas Peyrl (ORCID: https://orcid.org/0000-0002-5736-8231)
- Lisa Mayr (ORCID: https://orcid.org/0000-0002-6841-0749)
- Norman Mack
- Rebecca D Haase
- Daniela Lötsch
- A Silva
- Lisa Gabler-Pamer
- Rene Geyregger
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center Utrecht (NL)
- Comprehensive Cancer Center Vienna (AT)
- Hopp Children's Cancer Center Heidelberg (DE)
- Cancer Research Institute of the Slovak Academy of Sciences (SK)
- St Anna Children's Hospital (AT)
- Princess Máxima Center (NL)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Medical University of Vienna (AT)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1038/s43018-025-00964-9
- Citations
- 4
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 3.75