Porpiglia and Blau article featured on the cover of Science Advances

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. In a recent paper featured on the cover of Science Advances Helen Blau, Ermelinda Porpiglia, and colleagues describe a combined single-cell RNA sequencing, mass cytometry, and high-content imaging approach they applied to understand intratumoral heterogeneity of patient-derived RMS cultures. Their data revealed that the aggressive alveolar RMS subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth. Intriguingly, the scientists also identified a subpopulation of differentiated cells that lost proliferative potential and correlate with better outcomes. This finding is relevant to RMS patients, because though chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells, which can contribute to disease progression. The authors identified a combination of RAF and MEK inhibitors that potently inhibit tumor growth. Overall, this manuscript provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.