Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs.
Cell Rep Med
; 5(6): 101582, 2024 Jun 18.
Article
em En
| MEDLINE
| ID: mdl-38781959
ABSTRACT
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1WT1 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 EWSR1WT1 DNA-binding activity associates with most lineage-related states, in contrast to glycolytic and profibrotic states. Single-cell chromatin accessibility analysis suggests that EWSR1WT1 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Análise de Célula Única
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Microambiente Tumoral
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article