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Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma

Author

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  • Sara G. Danielli

    (University Children’s Hospital of Zurich)

  • Yun Wei

    (Massachusetts General Research Institute
    Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • Michael A. Dyer

    (St. Jude Children’s Research Hospital)

  • Elizabeth Stewart

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Heather Sheppard

    (St. Jude Children’s Research Hospital)

  • Marco Wachtel

    (University Children’s Hospital of Zurich)

  • Beat W. Schäfer

    (University Children’s Hospital of Zurich)

  • Anand G. Patel

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • David M. Langenau

    (Massachusetts General Research Institute
    Massachusetts General Hospital
    Harvard Stem Cell Institute)

Abstract

Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity is shared with human development has not been described. Using single-cell/nucleus RNA sequencing from patient tumors, patient-derived xenografts, primary in vitro cultures, and cell lines, we identify four dominant muscle-lineage cell states: progenitor, proliferative, differentiated, and ground cells. We stratify these RMS cells/nuclei along the continuum of human muscle development and show that they share expression patterns with fetal/embryonal myogenic precursors rather than postnatal satellite cells. Fusion-negative RMS (FN-RMS) have a discrete stem cell hierarchy that recapitulates fetal muscle development and contain therapy-resistant FN-RMS progenitors that share transcriptomic similarity with bipotent skeletal mesenchymal cells. Fusion-positive RMS have tumor-acquired cells states, including a neuronal cell state, that are not found in myogenic development. This work identifies previously underappreciated cell state heterogeneity including unique treatment-resistant and tumor-acquired cell states that differ across RMS subtypes.

Suggested Citation

  • Sara G. Danielli & Yun Wei & Michael A. Dyer & Elizabeth Stewart & Heather Sheppard & Marco Wachtel & Beat W. Schäfer & Anand G. Patel & David M. Langenau, 2024. "Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50527-2
    DOI: 10.1038/s41467-024-50527-2
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