ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution
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 huma...
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2025-06-01
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| Online Access: | https://doi.org/10.1038/s41467-025-60442-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Flavia W. de Faria |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-549d4fe2f7db480184d2718c171c3dd6 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-549d4fe2f7db480184d2718c171c3dd62025-08-20T02:37:58ZengNature PortfolioNature Communications2041-17232025-06-0116111910.1038/s41467-025-60442-9ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolutionFlavia W. de Faria0Nicole C. Riedel1Daniel Münter2Marta Interlandi3Carolin Göbel4Lea Altendorf5Mathis Richter6Viktoria Melcher7Christian Thomas8Rajanya Roy9Melanie Schoof10Ivan Bedzhov11Natalia Moreno12Monika Graf13Marc Hotfilder14Dörthe Holdhof15Wolfgang Hartmann16Ann-Katrin Bruns17Angela Brentrup18Friederike Liesche-Starnecker19Bruno Maerkl20Sarah Sandmann21Julian Varghese22Martin Dugas23Pedro H. Pinto24Sebastian T. Balbach25I-Na Lu26Claudia Rossig27Oliver Soehnlein28Aysegül Canak29Martin Ebinger30Martin Schuhmann31Jens Schittenhelm32Michael F. Frühwald33Ulrich Schüller34Thomas K. Albert35Carolin Walter36Jan M. Bruder37Kornelius Kerl38Department of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfInstitute for Experimental Pathology, Center for Molecular Biology of Inflammation, University of MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterInstitute of Neuropathology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfEmbryonic Self-Organization Research Group, Max Planck Institute for Molecular BiomedicineDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDivision of Translational Pathology, Gerhard-Domagk Institute of Pathology, University Hospital MünsterDepartment of Neurosurgery, University Hospital MünsterDepartment of Neurosurgery, University Hospital MünsterDepartment of Neuropathology, Pathology, Medical Faculty, University of AugsburgDepartment of Neuropathology, Pathology, Medical Faculty, University of AugsburgInstitute of Medical Informatics, Westphalian Wilhelms University MünsterInstitute of Medical Informatics, Westphalian Wilhelms University MünsterInstitute of Medical Informatics, Westphalian Wilhelms University MünsterDepartment of Pathology, Children’s Hospital of Brasilia Jose de AlencarDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterInstitute for Experimental Pathology, Center for Molecular Biology of Inflammation, University of MünsterDepartment of Hematology and Oncology, Children’s University Hospital Tübingen, and German Cancer Consortium (DKTK) TübingenDepartment of Neurosurgery, section of Pediatric Neurosurgery, University Hospital Tübingen, and German Cancer Consortium (DKTK) TübingenDepartment of Neurosurgery, section of Pediatric Neurosurgery, University Hospital Tübingen, and German Cancer Consortium (DKTK) TübingenDepartment of Neuropathology, University Medical Hospital, Eberhard Karls University TübingenSwabian Children’s Cancer Center, Pediatric and Adolescent Medicine, University Center AugsburgDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Hospital MünsterDepartment for Cell and Developmental Biology, Max Planck Institute for molecular BiomedicineDepartment of Pediatric Hematology and Oncology, University Hospital MünsterAbstract 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.https://doi.org/10.1038/s41467-025-60442-9 |
| spellingShingle | 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 ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution Nature Communications |
| title | ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution |
| title_full | ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution |
| title_fullStr | ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution |
| title_full_unstemmed | ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution |
| title_short | ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution |
| title_sort | etmr stem like state and chemo resistance are supported by perivascular cells at single cell resolution |
| url | https://doi.org/10.1038/s41467-025-60442-9 |
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