A convergent cell state of high-risk rhabdomyosarcoma

Somatic mutations often predict survival in childhood cancers, as exemplified in rhabdomyosarcoma, where FOXO1 gene fusion status is a key prognostic feature. We have discovered that cancer cells of lethal disease converge on a common cell state, irrespective of fusion status. The convergent cell state only partially overlapped with transcriptional effects of the FOXO1 fusion and unexpectedly exhibited neural features. We examined individual cancer cell transcriptomes and validated our findings by nuclear transcriptomics, chromatin accessibility, spatial transcriptomics, perturbation studies, and in previously published data sets. Our findings delineate a novel cell state of high-risk rhabdomyosarcoma cells that transcends conventional molecular and histological boundaries, and suggests an overarching disease phenotype. This could transform target discovery and inform clinical practice.