Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors.

Autor: Graf M; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Interlandi M; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany.; Institute of Medical Informatics, University of Münster, 48149, Münster, Germany., Moreno N; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Holdhof D; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany., Göbel C; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany., Melcher V; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Mertins J; Department of Neurology, Schlosspark-Klinik, 14059, Berlin, Germany.; Institute of Molecular Tumor Biology, University of Münster, 48149, Münster, Germany., Albert TK; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Kastrati D; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Alfert A; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Holsten T; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.; Institute of Molecular Tumor Biology, University of Münster, 48149, Münster, Germany., de Faria F; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany.; Department of Pediatric Hematology and Oncology, Children's Hospital of Brasìlia, 70684-831, Brasìlia, Brazil., Meisterernst M; Institute of Molecular Tumor Biology, University of Münster, 48149, Münster, Germany., Rossig C; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany., Warmuth-Metz M; Neuroradiological Reference Center, University Hospital Würzburg, Würzburg, Germany., Nowak J; Neuroradiological Reference Center, University Hospital Würzburg, Würzburg, Germany.; SRH Poliklinik Gera GmbH, Radiological Practice Gotha, Gotha, Germany., Meyer Zu Hörste G; Department of Neurology with Institute of Translational Neurology, University Hospital Münster, 48149, Münster, Germany., Mayère C; Department of Genetic Medicine and Development, University of Geneva, 1211, Geneva, Switzerland.; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211, Geneva, Switzerland., Nef S; Department of Genetic Medicine and Development, University of Geneva, 1211, Geneva, Switzerland.; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211, Geneva, Switzerland., Johann P; Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156, Augsburg, Germany.; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Frühwald MC; Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156, Augsburg, Germany., Dugas M; Institute of Medical Informatics, University of Münster, 48149, Münster, Germany.; Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany., Schüller U; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.; Research Institute Children's Cancer Center, 20251, Hamburg, Germany., Kerl K; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany. kornelius.kerl@ukmuenster.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Mar 22; Vol. 13 (1), pp. 1544. Date of Electronic Publication: 2022 Mar 22.
DOI: 10.1038/s41467-022-29152-4
Abstrakt: Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.
(© 2022. The Author(s).)
Databáze: MEDLINE
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