Epigenetic and transcriptional heterogeneity define osteosarcoma subtypes and establish targetable vulnerabilities [multiomics]

Osteosarcoma is a genomically complex tumor with structural rearrangements, aneuploidy, and chromosomal alterations, resulting in significant intertumoral heterogeneity. This complexity hampers the identification of key oncogenic pathways and subtypes. We hypothesized that chromatin accessibility could uncover molecular features to clarify their transcriptional programs, suggesting new therapies. Using ATAC-seq, H3K27ac profiling, and single-cell multiome analysis, we identified two distinct cellular states in osteosarcoma driven by unique transcription factor networks linked to normal bone development. These subtypes can be detected in patient samples via a specific gene expression signature with prognostic value.