Spatially-Resolved Multiomic Atlas of Leiomyosarcoma Identifies Two Clinically Relevant Epigenetically-Driven Cell States [scMultiomic]

Leiomyosarcoma (LMS) is a malignant smooth muscle tumor characterized by substantial clinical and molecular heterogeneity. To investigate the cellular and regulatory landscape of LMS at single-cell resolution, we performed single-nucleus multiome sequencing to jointly profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) in 16 untreated primary leiomyosarcoma tumors arising from retroperitoneal, extremity, and uterine sites. After quality control, 94,439 nuclei were analyzed, revealing diverse tumor and microenvironmental cell populations including macrophages, T cells, and endothelial cells. Malignant cells segregated predominantly into two major transcriptional and epigenetic states: a dedifferentiated mesenchymal-like subtype (MES) and a differentiated smooth muscle cell–like subtype (SMC). Integration of transcriptomic and chromatin accessibility profiles identified distinct regulatory programs underlying these states, including enrichment of NFI transcription factor motifs in MES cells and AP-1 family motifs in SMC cells. These data provide a comprehensive multiomic resource for understanding tumor heterogeneity and regulatory mechanisms in leiomyosarcoma.