Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

Key Points Rhabdomyosarcoma (RMS) is a soft tissue malignancy composed of neoplastic cells that morphologically resemble skeletal muscle-lineage precursor cells. High-risk RMS has a dismal prognosis, and treatments for this condition have not improved for three decades now. RMS is a heterogeneous disease composed of four subtypes. Embryonal RMS (ERMS), the most common subtype, associates with various tumour-promoting signalling pathways (for example, RAS and Hedgehog) and/or loss of tumour surveillance (for example, TP53 mutations). Pleomorphic RMS is very aggressive and occurs during the sixth and seventh decades of life. Spindle cell/sclerosing RMS affects both children and adults, with favourable and unfavourable prognoses, respectively. Alveolar RMS (ARMS), which is notoriously aggressive, is a genetically distinct disease driven by the PAX3–FOXO1 and PAX7–FOXO1 chimeric oncoproteins that are unique to ARMS. Understanding the cell (or cells) of origin for RMS is complex, reflecting the fact that multiple precursor cells can give rise to RMS in mouse models. To relieve a bottleneck that has existed in the design of new RMS therapies, an impressive array of new RMS model systems, spanning the evolutionary spectrum from flies to fish to mammals, have recently been developed; these new models have proven successful in uncovering new pathogenic mechanisms of RMS. Moreover, RMS gene discovery prompted by these diverse yet remarkably complementary model systems is inspiring new possibilities for targeted RMS therapy. These models also point to viable approaches for the genetic and molecular dissection of other clinically problematic non-RMS sarcomas. This Review discusses what we have learned about the biology of rhabdomyosarcoma using various model systems, and how these models might be used to discover new targetable pathogenic mechanisms. Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outc