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
- Kornelius Kerl
2025-06-25
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.