Journal Article

DKFZ-2025-01291

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution.

de Faria, F. W. ; Riedel, N. C. ; Münter, D. ; Interlandi, M. ; Göbel, C. ; Altendorf, L. ; Richter, M. ; Melcher, V. ; Thomas, C. ; Roy, R. ; Schoof, M. ; Bedzhov, I. ; Moreno, N. ; Graf, M. ; Hotfilder, M. ; Holdhof, D. ; Hartmann, W. ; Bruns, A.-K. ; Brentrup, A. ; Liesche-Starnecker, F. ; Maerkl, B. ; Sandmann, S. ; Varghese, J. ; Dugas, M. ; Pinto, P. H. ; Balbach, S. T. ; Lu, I.-N. ; Rossig, C. ; Soehnlein, O. ; Canak, A.DKFZ* ; Ebinger, M.DKFZ* ; Schuhmann, M.DKFZ* ; Schittenhelm, J. ; Frühwald, M. F. ; Schüller, U. ; Albert, T. K. ; Walter, C. ; Bruder, J. M. ; Kerl, K.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-60442-9

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.

Keyword(s): Humans (MeSH) ; Pericytes: metabolism (MeSH) ; Pericytes: pathology (MeSH) ; Animals (MeSH) ; Single-Cell Analysis (MeSH) ; Mice (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Receptor, Platelet-Derived Growth Factor beta: metabolism (MeSH) ; Receptor, Platelet-Derived Growth Factor beta: genetics (MeSH) ; Tumor Microenvironment: genetics (MeSH) ; Signal Transduction (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: metabolism (MeSH) ; Brain Neoplasms: drug therapy (MeSH) ; Neoplastic Stem Cells: metabolism (MeSH) ; Neoplastic Stem Cells: pathology (MeSH) ; Cell Differentiation (MeSH) ; Cell Communication (MeSH) ; Organoids (MeSH) ; Platelet-Derived Growth Factor: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Receptor, Platelet-Derived Growth Factor beta ; Platelet-Derived Growth Factor

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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