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

Monika Graf, Marta Interlandi, Natalia Moreno, Dörthe Holdhof, Carolin Göbel, Viktoria Melcher, Julius Mertins, Thomas K. Albert, Dennis Kastrati, Amelie Alfert, Till Holsten, Flavia de Faria, Michael Meisterernst, Claudia Rossig, Monika Warmuth-Metz, Johannes Nowak, Gerd Meyer zu Hörste, Chloe Mayère, Serge Nef, Pascal Johann, Michael C. Frühwald, Martin Dugas, Ulrich Schüller and Kornelius Kerl ()
Additional contact information
Monika Graf: University Children’s Hospital Münster
Marta Interlandi: University Children’s Hospital Münster
Natalia Moreno: University Children’s Hospital Münster
Dörthe Holdhof: University Medical Center Hamburg-Eppendorf
Carolin Göbel: University Medical Center Hamburg-Eppendorf
Viktoria Melcher: University Children’s Hospital Münster
Julius Mertins: Department of Neurology, Schlosspark-Klinik
Thomas K. Albert: University Children’s Hospital Münster
Dennis Kastrati: University Children’s Hospital Münster
Amelie Alfert: University Children’s Hospital Münster
Till Holsten: University Medical Center Hamburg-Eppendorf
Flavia de Faria: University Children’s Hospital Münster
Michael Meisterernst: University of Münster
Claudia Rossig: University Children’s Hospital Münster
Monika Warmuth-Metz: University Hospital Würzburg
Johannes Nowak: University Hospital Würzburg
Gerd Meyer zu Hörste: University Hospital Münster
Chloe Mayère: University of Geneva
Serge Nef: University of Geneva
Pascal Johann: Paediatric and Adolescent Medicine, University Medical Center Augsburg
Michael C. Frühwald: Paediatric and Adolescent Medicine, University Medical Center Augsburg
Martin Dugas: University of Münster
Ulrich Schüller: University Medical Center Hamburg-Eppendorf
Kornelius Kerl: University Children’s Hospital Münster

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29152-4

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DOI: 10.1038/s41467-022-29152-4

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