ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution

Flavia W. de Faria, Nicole C. Riedel, Daniel Münter, Marta Interlandi, Carolin Göbel, Lea Altendorf, Mathis Richter, Viktoria Melcher, Christian Thomas, Rajanya Roy, Melanie Schoof, Ivan Bedzhov, Natalia Moreno, Monika Graf, Marc Hotfilder, Dörthe Holdhof, Wolfgang Hartmann, Ann-Katrin Bruns, Angela Brentrup, Friederike Liesche-Starnecker, Bruno Maerkl, Sarah Sandmann, Julian Varghese, Martin Dugas, Pedro H. Pinto, Sebastian T. Balbach, I-Na Lu, Claudia Rossig, Oliver Soehnlein, Aysegül Canak, Martin Ebinger, Martin Schuhmann, Jens Schittenhelm, Michael F. Frühwald, Ulrich Schüller, Thomas K. Albert, Carolin Walter, Jan M. Bruder and Kornelius Kerl ()
Additional contact information
Flavia W. de Faria: University Hospital Münster
Nicole C. Riedel: University Hospital Münster
Daniel Münter: University Hospital Münster
Marta Interlandi: University Hospital Münster
Carolin Göbel: University Medical Center Hamburg-Eppendorf
Lea Altendorf: University Medical Center Hamburg-Eppendorf
Mathis Richter: University of Münster
Viktoria Melcher: University Hospital Münster
Christian Thomas: University Hospital Münster
Rajanya Roy: University Hospital Münster
Melanie Schoof: University Medical Center Hamburg-Eppendorf
Ivan Bedzhov: Max Planck Institute for Molecular Biomedicine
Natalia Moreno: University Hospital Münster
Monika Graf: University Hospital Münster
Marc Hotfilder: University Hospital Münster
Dörthe Holdhof: University Medical Center Hamburg-Eppendorf
Wolfgang Hartmann: University Hospital Münster
Ann-Katrin Bruns: University Hospital Münster
Angela Brentrup: University Hospital Münster
Friederike Liesche-Starnecker: University of Augsburg
Bruno Maerkl: University of Augsburg
Sarah Sandmann: Westphalian Wilhelms University Münster
Julian Varghese: Westphalian Wilhelms University Münster
Martin Dugas: Westphalian Wilhelms University Münster
Pedro H. Pinto: Children’s Hospital of Brasilia Jose de Alencar
Sebastian T. Balbach: University Hospital Münster
I-Na Lu: University Hospital Münster
Claudia Rossig: University Hospital Münster
Oliver Soehnlein: University of Münster
Aysegül Canak: and German Cancer Consortium (DKTK) Tübingen
Martin Ebinger: and German Cancer Consortium (DKTK) Tübingen
Martin Schuhmann: and German Cancer Consortium (DKTK) Tübingen
Jens Schittenhelm: Eberhard Karls University Tübingen
Michael F. Frühwald: University Center Augsburg
Ulrich Schüller: University Medical Center Hamburg-Eppendorf
Thomas K. Albert: University Hospital Münster
Carolin Walter: University Hospital Münster
Jan M. Bruder: Max Planck Institute for molecular Biomedicine
Kornelius Kerl: University Hospital Münster

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Embryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+ pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.

Date: 2025
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DOI: 10.1038/s41467-025-60442-9

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