Single cell RNA sequencing identifies a novel tenogenic heterologous differentiation in endometrial carcinosarcomas
This study presents a single-cell RNA sequencing (scRNAseq) analysis of six carcinosarcomas and two normal endometrial samples, profiling over 96,000 cells. By integrating transcriptomic data with inferred copy number variations (CNVs), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH), we resolve the complex cellular architecture and differentiation dynamics of these tumors. We identify distinct lineage-specific programs and uncover heterologous differentiation trajectories—including rhabdomyogenic, osteogenic, and a previously undescribed tenogenic lineage defined by SCX, MKX, and TNMD expression. Our results reveal that carcinosarcomas exhibit multilineage plasticity within their mesenchymal component and highlight the power of single-cell analysis to refine tumor classification and uncover hidden developmental programs. Overall design: Six carcinosarcoma samples and two normal endometrial controls were analyzed using scRNAseq. Tumors were dissociated and processed for droplet-based scRNAseq, followed by integration with inferred CNVs, IHC, and FISH validation. The study aimed to characterize epithelial and mesenchymal lineages, identify novel differentiation programs, and explore the genomic architecture underlying carcinosarcoma plasticity.