Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs - Inserm - Institut national de la santé et de la recherche médicale
Article Dans Une Revue Cell Reports Medicine Année : 2024

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

Résumé

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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inserm-04658391 , version 1 (22-07-2024)

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Clémence Henon, Julien Vibert, Thomas Eychenne, Nadège Gruel, Léo Colmet-Daage, et al.. Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs. Cell Reports Medicine, 2024, 5 (6), pp.101582. ⟨10.1016/j.xcrm.2024.101582⟩. ⟨inserm-04658391⟩
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