Abstract Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive sarcomas driven by the EWSR1::WT1 fusion oncoprotein (FP) and marked by poor long-term survival. Despite a relatively quiet genome with a single known oncogenic driver, DSRCTs display striking transcriptional heterogeneity and express markers from multiple lineages, epithelial, mesenchymal, myogenic, and neural. DSRCTs show a strong male predominance, suggesting a potential role for sex-specific regulatory mechanisms, including androgen receptor (AR) signaling. To investigate the molecular basis of this complexity, we generated a comprehensive, multi-modal atlas of DSRCT, integrating transcriptomic, epigenomic, and spatial omics data (10x Genomics). We focused on dissecting the regulatory architecture shaped by the EWSR1::WT1 fusion and transcription factors such as AR, aiming to uncover mechanisms of lineage specification and therapeutic vulnerabilities. We hypothesized that epigenetic regulation of the EWSR1::WT1 FP contributes to this lineage divergence. To explore FP activity, we found that neogenes (non-coding RNA FP targets) and known FP-regulated genes were more highly expressed in NE-lineage tumors, suggesting that FP affects lineage type. Spatial transcriptomic analysis revealed intratumoral heterogeneity, with distinct clusters of epithelial (AR+, cytokeratin+) and non-epithelial tumor cells. Despite phenotypic differences, all tumor cells expressed neogenes, as confirmed by RNA in situ hybridization (RNAScope). Epigenetic profiling showed enrichment of Forkhead TFs (FOXA1/2). FOXA2 was associated with NE, and AR/GRHL2 were associated with epithelial lineages. CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3489.
Truong et al. (2026) studied this question.