High-Risk Rhabdomyosarcomas Feature a Convergent Cell State

Abstract Somatic mutations often predict survival in childhood cancers, as exemplified in rhabdomyosarcoma (RMS), in which FOXO1 gene fusion status is a key prognostic feature. In this study, we examined single-cell transcriptomes and discovered that cancer cells of lethal disease converge on a common cell state with a shared transcriptional landscape, irrespective of fusion status. Nuclear transcriptomics, chromatin accessibility, spatial transcriptomics, perturbation studies, and previously published datasets validated the overarching high-risk cell state. The convergent cell state only partially overlapped with transcriptional effects of the FOXO1 fusion and unexpectedly exhibited neural features. Overall, these findings delineate a cell state of high-risk RMS cells that transcends conventional molecular and histologic boundaries, suggesting an overarching disease phenotype that could transform target discovery and inform clinical practice. Significance: Defining a convergent cell state of high-risk rhabdomyosarcoma that transcends existing histological and molecular features predictive of outcome provides biological insights into aggressive disease and uncovers potential biomarkers and therapeutic targets.