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<p>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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月25日

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  • 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

摘要

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.