Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells

• Mouse RMS (mRMS) can be initiated in Pax7+MyoD− muscle stem cells
• Mouse UPS (mUPS) can be initiated in Pax7+MyoD+ myogenic progenitors
• mUPS cluster separately from mRMS by PCA and hierarchical clustering
• mUPS and mRMS enrich in their human counterparts by GSEA

SummaryRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, whereas undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas diagnosed in adults. To investigate the myogenic cell(s) of origin of these sarcomas, we used Pax7-CreER and MyoD-CreER mice to transform Pax7+ and MyoD+ myogenic progenitors by expressing oncogenic KrasG12D and deleting Trp53 in vivo. Pax7-CreER mice developed RMS and UPS, whereas MyoD-CreER mice developed UPS. Using gene set enrichment analysis, RMS and UPS each clustered specifically within their human counterparts. These results suggest that RMS and UPS have distinct and overlapping cells of origin within the muscle lineage. Taking them together, we have established mouse models of soft tissue sarcoma from muscle stem and progenitor cells.

Graphical AbstractFigure optionsDownload as PowerPoint slide