Spatial transcriptomic profiling reveals heterogeneity in desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive soft tissue sarcoma driven by the chimeric fusion protein EWSR1-WT1 that modulates oncogenic gene expression programs in DSRCT tumor cells. Despite this defined molecular driver, treatment response and survival outcomes vary substantially between DSRCT patients (5-year survival ~ 15%). We hypothesize that treatment outcome variability reflects heterogeneity in tumor cell phenotypic states, microenvironmental architecture, and signaling networks. Here we profiled seven peritoneal and lymph node metastatic tumor sites across four DSRCT patients using Xenium 5K spatial transcriptomics on tissue microarrays (1,383,406 cells). We integrated snRNA-seq data from 15 DSRCT samples (251,087 cells) for cell type annotation, identifying patient-specific tumor subtypes through per-patient Leiden clustering (resolution=0.2) and CAF subtypes through marker gene scoring. This revealed 14 patient-specific tumor subtypes (3-4 per patient), three CAF subtypes (apCAFs, myCAFs, iCAFs), macrophages, T cells, and endothelial cells.