Dataset Information

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

ABSTRACT: In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.

SUBMITTER: John L

PROVIDER: S-EPMC10435504 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

John Lukas L Poos Alexandra M AM Brobeil Alexander A Schinke Carolina C Huhn Stefanie S Prokoph Nina N Lutz Raphael R Wagner Barbara B Zangari Maurizio M Tirier Stephan M SM Mallm Jan-Philipp JP Schumacher Sabrina S Vonficht Dominik D Solé-Boldo Llorenç L Quick Sabine S Steiger Simon S Przybilla Moritz J MJ Bauer Katharina K Baumann Anja A Hemmer Stefan S Rehnitz Christoph C Lückerath Christian C Sachpekidis Christos C Mechtersheimer Gunhild G Haberkorn Uwe U Dimitrakopoulou-Strauss Antonia A Reichert Philipp P Barlogie Bart B Müller-Tidow Carsten C Goldschmidt Hartmut H Hillengass Jens J Rasche Leo L Haas Simon F SF van Rhee Frits F Rippe Karsten K Raab Marc S MS Sauer Sandra S Weinhold Niels N

Nature communications 20230817 1

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of sp ...[more]

PMID: 37591845

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Project description:BackgroundCardiac myxoma (CM) is the most common (58%-80%) type of primary cardiac tumours. Currently, there is a need to develop medical therapies, especially for patients not physically suitable for surgeries. However, the mechanisms that shape the tumour microenvironment (TME) in CM remain largely unknown, which impedes the development of targeted therapies. Here, we aimed to dissect the TME in CM at single-cell and spatial resolution.MethodsWe performed single-cell transcriptomic sequencing and Visium CytAssist spatial transcriptomic (ST) assays on tumour samples from patients with CM. A comprehensive analysis was performed, including unsupervised clustering, RNA velocity, clonal substructure inference of tumour cells and cell-cell communication.ResultsUnsupervised clustering of 34 759 cells identified 12 clusters, which were assigned to endothelial cells (ECs), mesenchymal stroma cells (MSCs), and tumour-infiltrating immune cells. Myxoma tumour cells were found to encompass two closely related phenotypic states, namely, EC-like tumour cells (ETCs) and MSC-like tumour cells (MTCs). According to RNA velocity, our findings suggest that ETCs may be directly differentiated from MTCs. The immune microenvironment of CM was found to contain multiple factors that promote immune suppression and evasion, underscoring the potential of using immunotherapies as a treatment option. Hyperactive signals sent primarily by tumour cells were identified, such as MDK, HGF, chemerin, and GDF15 signalling. Finally, the ST assay uncovered spatial features of the subclusters, proximal cell-cell communication, and clonal evolution of myxoma tumour cells.ConclusionsOur study presents the first comprehensive characterisation of the TME in CM at both single-cell and spatial resolution. Our study provides novel insight into the differentiation of myxoma tumour cells and advance our understanding of the TME in CM. Given the rarity of cardiac tumours, our study provides invaluable datasets and promotes the development of medical therapies for CM.

Dataset Information

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

Publications

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

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