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

Henon, Clémence; Vibert, Julien; Eychenne, Thomas; Gruel, Nadège; Colmet-Daage, Léo; Ngo, Carine; Garrido, Marlène; Dorvault, Nicolas; Marques Da Costa, Maria Eugenia; Marty, Virginie; Signolle, Nicolas; Marchais, Antonin; Herbel, Noé; Kawai-Kawachi, Asuka; Lenormand, Madison; Astier, Clémence; Chabanon, Roman; Verret, Benjamin; Bahleda, Rastislav; Le Cesne, Axel; Mechta-Grigoriou, Fatima; Faron, Matthieu; Honoré, Charles; Delattre, Olivier; Waterfall, Joshua J.; Watson, Sarah; Postel-Vinay, Sophie

doi:10.1016/j.xcrm.2024.101582

Cited by 4 publications

References 91 publications

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Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Geyer,

Ritter,

Kinn-Gurzo

et al. 2024

Preprint

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Desmoplastic small round cell tumor (DSRCT) is a highly aggressive cancer predominantly occurring in male adolescents and young adults. The lack of a comprehensive understanding on the biology of the disease is paralleled by its dismal survival rates (5–20%). To overcome this challenge, we first identified and prioritized urgently needed resources for clinicians and researchers. Thus, we established genome-wide single-cell RNA-sequencing and bulk proteomic data of in vitro and in vivo-generated knockdown models of the pathognomonic DSRCT fusion oncoprotein (EWSR1::WT1) and combined them with an original systems-biology-based pipeline including patient data and the largest histology collection of DSRCTs and morphological mimics available to date. These novel tools were enriched with curated public datasets including patient- and cell line-derived ChIP-seq, bulk and single-cell RNA-seq studies resulting in a multi-model and multi-omic toolbox for discovery analyses. As a proof of concept, our approach revealed the alpha-2/delta subunit of the voltage-dependent calcium channel complex, CACNA2D2, as a highly overexpressed, super-enhancer driven, direct target of EWSR1::WT1. Single-cell and bulk-level analyses of patient samples and xenografted cell lines highlighted CACNA2D2 as a critical component of our newly established EWSR1::WT1 oncogenic signature, that can be employed to robustly identify DSRCT in reference sets. Finally, we show that CACNA2D2 is a highly sensitive and specific single biomarker for fast, simple, and cost-efficient diagnosis of DSRCT. Collectively, we establish a large-scale multi-omics dataset for this devastating disease and provide a blueprint of how such toolbox can be used to identify new and clinically relevant diagnostic markers, which may significantly reduce misdiagnoses, and thus improve patient care.

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Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Geyer,

Ritter,

Kinn-Gurzo

et al. 2024

Preprint

Self Cite

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Multi-omic profiling identifies malignant subpopulations and a hypoxia-driven angiogenic axis as therapeutic vulnerabilities in sinonasal squamous cell carcinoma

You,

Park,

Jang

et al. 2024

Preprint

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Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy with limited treatment options, necessitating comprehensive molecular characterization to uncover actionable therapeutic targets. Here, we integrate bulk and single-cell transcriptomics, epigenomics, and DNA methylation profiling to construct a detailed molecular and cellular landscape of SNSCC. Our analysis identifies five transcriptionally and epigenetically distinct malignant subpopulations, including hypoxic (TC1) and proliferative (TC2) clusters, with TC1 showing significant association with poor clinical outcomes. We uncover a hypoxia-driven angiogenic axis, wherein TC1 cells secrete adrenomedullin (ADM), MIF, and VEGFA to activate endothelial tip cells, fostering tumor angiogenesis. Epigenetic reprogramming, characterized by alterations in DNA methylation and chromatin accessibility, underpins these transcriptional programs, with AP-1 transcription factors emerging as key regulators. Notably, ADM expression is epigenetically controlled, correlates with advanced clinical stage, and predicts reduced survival in head and neck cancer patients. This multi-omic study highlights the tumor heterogeneity and microenvironmental interactions driving SNSCC progression, revealing epigenetically regulated pathways as promising therapeutic targets for future intervention.

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Advances in targeting cancer-associated fibroblasts through single-cell spatial transcriptomic sequencing

Lyu,

Gu,

Wang

et al. 2024

Biomark Res

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Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and are related to tumor proliferation, metastasis, relapse, and drug resistance. With the development of sequencing technologies, single-cell RNA sequencing has become a popular method for identifying CAFs in the tumor microenvironment. Whereas the drawbacks of CAFs, such as the lack of a spatial landscape, still exist, recent research has utilized spatial transcriptomics combined with single-cell RNA sequencing to address this issue. These multiomics analyses can resolve the single-cell resolution problem in spatial transcriptomics. In this review, we summarized the recent literature regarding the targeting of CAFs to address drug resistance, angiogenesis, metabolic reprogramming and metastasis in tumor tissue.

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

Cited by 4 publications

References 91 publications

Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Multi-omic profiling identifies malignant subpopulations and a hypoxia-driven angiogenic axis as therapeutic vulnerabilities in sinonasal squamous cell carcinoma

Advances in targeting cancer-associated fibroblasts through single-cell spatial transcriptomic sequencing

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