Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells
Abstract Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the sig...
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-80858-5 |
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| author | Sen Lin Huimin Zhang Ruiqi Zhao Zhulin Wu Weiqing Zhang Mengjiao Yu Bei Zhang Lanyue Ma Danfei Li Lisheng Peng Weijun Luo |
| author_facet | Sen Lin Huimin Zhang Ruiqi Zhao Zhulin Wu Weiqing Zhang Mengjiao Yu Bei Zhang Lanyue Ma Danfei Li Lisheng Peng Weijun Luo |
| author_sort | Sen Lin |
| collection | DOAJ |
| description | Abstract Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation. |
| format | Article |
| id | doaj-art-349504a4f65e463fb56b1dba0ee91d87 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-349504a4f65e463fb56b1dba0ee91d872025-08-20T02:49:17ZengNature PortfolioScientific Reports2045-23222024-11-0114111710.1038/s41598-024-80858-5Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cellsSen Lin0Huimin Zhang1Ruiqi Zhao2Zhulin Wu3Weiqing Zhang4Mengjiao Yu5Bei Zhang6Lanyue Ma7Danfei Li8Lisheng Peng9Weijun Luo10The Fourth Clinical Medical College, Guangzhou University of Chinese MedicineThe First Clinical Medical College, Guangzhou University of Chinese MedicineThe Fourth Clinical Medical College, Guangzhou University of Chinese MedicineDepartment of Traditional Chinese Medicine, People’s Hospital of LonghuaDepartment of Traditional Chinese Medicine, People’s Hospital of LonghuaThe Fourth Clinical Medical College, Guangzhou University of Chinese MedicineThe Fourth Clinical Medical College, Guangzhou University of Chinese MedicineThe Fourth Clinical Medical College, Guangzhou University of Chinese MedicineThe Fourth Clinical Medical College, Guangzhou University of Chinese MedicineDepartment of Hepatology, Shenzhen Traditional Chinese Medicine HospitalDepartment of Traditional Chinese Medicine, People’s Hospital of LonghuaAbstract Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation.https://doi.org/10.1038/s41598-024-80858-5Pan-cancerDistant metastasisMast cellsHMG-CoA reductase inhibitorsMulti-omics |
| spellingShingle | Sen Lin Huimin Zhang Ruiqi Zhao Zhulin Wu Weiqing Zhang Mengjiao Yu Bei Zhang Lanyue Ma Danfei Li Lisheng Peng Weijun Luo Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells Scientific Reports Pan-cancer Distant metastasis Mast cells HMG-CoA reductase inhibitors Multi-omics |
| title | Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells |
| title_full | Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells |
| title_fullStr | Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells |
| title_full_unstemmed | Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells |
| title_short | Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells |
| title_sort | single cell multiomics reveals simvastatin inhibits pan cancer epithelial mesenchymal transition via the mek erk pathway in xbp1 mast cells |
| topic | Pan-cancer Distant metastasis Mast cells HMG-CoA reductase inhibitors Multi-omics |
| url | https://doi.org/10.1038/s41598-024-80858-5 |
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