Developmental Heterogeneity of Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a pediatric embryonal solid tumor and the most common pediatric soft tissue sarcoma. The histology and transcriptome of RMS resemble skeletal muscle progenitor cells that have failed to terminally differentiate. Thus, RMS is typically thought to arise from corrupted skeletal muscle progenitor cells during development. However, RMS can occur in body regions devoid of skeletal muscle, suggesting the potential for nonmyogenic cells of origin. Here, we discuss the interplay between RMS driver mutations and cell(s) of origin with an emphasis on driving location specificity. Additionally, we discuss the mechanisms governing RMS transformation events and tumor heterogeneity through the lens of transcriptional networks and epigenetic control. Finally, we reimagine Waddington's developmental landscape to include a plane of transformation connecting distinct lineage landscapes to more accurately reflect the phenomena observed in pediatric cancers.