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

Sara G. Danielli, Yun Wei, Michael A. Dyer, Elizabeth Stewart, Heather Sheppard, Marco Wachtel (), Beat W. Schäfer (), Anand G. Patel () and David M. Langenau ()
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Sara G. Danielli: University Children’s Hospital of Zurich
Yun Wei: Massachusetts General Research Institute
Michael A. Dyer: St. Jude Children’s Research Hospital
Elizabeth Stewart: 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
David M. Langenau: Massachusetts General Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50527-2

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