Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs
Clémence Henon, Julien Vibert, Thomas Eychenne, Nadège Gruel, Léo Colmet-Daage, Carine Ngo, Marlène Garrido, Nicolas Dorvault, Maria Eugénia Marques Da Costa, Virginie Marty, Nicolas Signolle, Antonin Marchais, Noé Herbel, Asuka Kawai-Kawachi, Madison M. Lenormand, Clémence Astier, Roman M. Chabanon, Benjamin Verret, Rastislav Bahleda, Axel Le Cesne, Fatima Mechta‐Grigoriou, Matthieu Faron, Charles Honoré, Olivier Delattre, Joshua J. Waterfall, Sarah Watson, Sophie Postel‐Vinay
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.