Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs
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22 mai 2024
- handle: 10670/1.uc983u
- inserm-04658391
- doi: 10.1016/j.xcrm.2024.101582
- PUBMED: 38781959
- PUBMEDCENTRAL: PMC11228554
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.xcrm.2024.101582
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info:eu-repo/semantics/altIdentifier/pmid/38781959
info:eu-repo/semantics/OpenAccess
Mots-clés
EWSR1::WT1 cancer-associated fibroblasts desmoplastic small round cell tumor microenvironment molecular and cellular heterogeneity plasticity sarcoma single-cell RNA-sequencing spatial transcriptomics transcription factor -bio]/CancerSujets proches
Statistical data Cases, clinical reports, statistics Speech--Transcription Language and languages--Transcription Transcribing Statistical data Statistical analysis Statistical methods Statistical science TranscribingCiter ce document
Clémence Henon et al., « Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs », HALSHS : archive ouverte en Sciences de l’Homme et de la Société, ID : 10.1016/j.xcrm.2024.101582
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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.