Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma.
• Its unique oncogenic driver, EWSR1::WT1, leads to polyphenotypic differentiation of unknown origin.

Purpose of the Study:

• To investigate the cellular heterogeneity and differentiation mechanisms in DSRCT.
• To explore the roles of the EWSR1::WT1 oncogene and tumor microenvironment in DSRCT biology.

Main Methods:

• Single-cell multi-omics (transcriptomics, epigenomics) on 12 DSRCT samples.
• In vitro modeling and spatial transcriptomics.
• Analysis of tumor cell subpopulations and microenvironmental factors.

Main Results:

• DSRCT cells form subpopulations with overlapping lineage and metabolic programs.
• EWSR1::WT1 activity correlates with lineage states, while hypoxia influences glycolytic/profibrotic states.
• An epithelial signature identified via single-cell transcriptomics predicts improved patient survival.

Conclusions:

• DSRCT heterogeneity arises from both cell-intrinsic EWSR1::WT1 activity and extrinsic microenvironmental cues.
• Understanding these subpopulations and their regulation is crucial for DSRCT treatment strategies.
• An epithelial signature may serve as a prognostic biomarker for DSRCT patients.