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

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

Cell Rep Med

ATIP-Avenir INSERM and ERC StG Group, Equipe labellisée ARC Recherche Fondamentale, INSERM U981, Gustave Roussy, Paris Saclay University, Villejuif, France; Drug Development Department, DITEP, Gustave Roussy, Villejuif, France; University College of London, Cancer Institute, London, UK. Electronic address:

Published: June 2024

AI Article Synopsis

  • Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive type of sarcoma caused by a specific genetic fusion known as EWSR1::WT1.
  • Researchers analyzed samples from patients using advanced techniques and found that DSRCT cells form distinct subpopulations with complex transcriptional behaviors based on lineage and metabolism.
  • The study also uncovered that certain tumor environments and a specific genetic signature are linked to better patient survival, indicating potential clinical implications for treatment approaches.

Article Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1::WT1 chimeric transcription factor. Despite this unique oncogenic driver, DSRCT displays a polyphenotypic differentiation of unknown causality. Using single-cell multi-omics on 12 samples from five patients, we find that DSRCT tumor cells cluster into consistent subpopulations with partially overlapping lineage- and metabolism-related transcriptional programs. In vitro modeling shows that high EWSR1::WT1 DNA-binding activity associates with most lineage-related states, in contrast to glycolytic and profibrotic states. Single-cell chromatin accessibility analysis suggests that EWSR1::WT1 binding site variability may drive distinct lineage-related transcriptional programs, supporting some level of cell-intrinsic plasticity. Spatial transcriptomics reveals that glycolytic and profibrotic states specifically localize within hypoxic niches at the periphery of tumor cell islets, suggesting an additional role of tumor cell-extrinsic microenvironmental cues. We finally identify a single-cell transcriptomics-derived epithelial signature associated with improved patient survival, highlighting the clinical relevance of our findings.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228554PMC
http://dx.doi.org/10.1016/j.xcrm.2024.101582DOI Listing

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