Pan-cancer drivers of metastasis
Abstract Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analys...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02182-w |
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| author | Ryan Lusby Engin Demirdizen Mohammed Inayatullah Paramita Kundu Oscar Maiques Ziyi Zhang Mikkel Green Terp Victoria Sanz-Moreno Vijay K. Tiwari |
| author_facet | Ryan Lusby Engin Demirdizen Mohammed Inayatullah Paramita Kundu Oscar Maiques Ziyi Zhang Mikkel Green Terp Victoria Sanz-Moreno Vijay K. Tiwari |
| author_sort | Ryan Lusby |
| collection | DOAJ |
| description | Abstract Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analysis encompassing over two hundred patients with metastatic and non-metastatic tumours across six cancer types. Our analysis revealed a prognostic core gene signature that provides insights into the intricate cellular dynamics and gene regulatory networks driving metastasis progression at the pan-cancer and single-cell level. Notably, the dissection of transcription factor networks active across different stages of metastasis, combined with functional perturbation, identified SP1 and KLF5 as key regulators, acting as drivers and suppressors of metastasis, respectively, at critical steps of this transition across multiple cancer types. Through in vivo and in vitro loss of function of SP1 in cancer cells, we revealed its role in driving cancer cell survival, invasive growth, and metastatic colonisation. Furthermore, tumour cells and the microenvironment increasingly engage in communication through WNT signalling as metastasis progresses, driven by SP1. Further validating these observations, a drug repurposing analysis identified distinct FDA-approved drugs with anti-metastasis properties, including inhibitors of WNT signalling across various cancers. |
| format | Article |
| id | doaj-art-5ac77975c36c4deab27ae534361e6a28 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-5ac77975c36c4deab27ae534361e6a282025-01-05T12:10:22ZengBMCMolecular Cancer1476-45982025-01-0124113010.1186/s12943-024-02182-wPan-cancer drivers of metastasisRyan Lusby0Engin Demirdizen1Mohammed Inayatullah2Paramita Kundu3Oscar Maiques4Ziyi Zhang5Mikkel Green Terp6Victoria Sanz-Moreno7Vijay K. Tiwari8Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University BelfastInstitute for Molecular Medicine, University of Southern DenmarkInstitute for Molecular Medicine, University of Southern DenmarkThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer ResearchThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer ResearchWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University BelfastInstitute for Molecular Medicine, University of Southern DenmarkThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer ResearchWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University BelfastAbstract Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analysis encompassing over two hundred patients with metastatic and non-metastatic tumours across six cancer types. Our analysis revealed a prognostic core gene signature that provides insights into the intricate cellular dynamics and gene regulatory networks driving metastasis progression at the pan-cancer and single-cell level. Notably, the dissection of transcription factor networks active across different stages of metastasis, combined with functional perturbation, identified SP1 and KLF5 as key regulators, acting as drivers and suppressors of metastasis, respectively, at critical steps of this transition across multiple cancer types. Through in vivo and in vitro loss of function of SP1 in cancer cells, we revealed its role in driving cancer cell survival, invasive growth, and metastatic colonisation. Furthermore, tumour cells and the microenvironment increasingly engage in communication through WNT signalling as metastasis progresses, driven by SP1. Further validating these observations, a drug repurposing analysis identified distinct FDA-approved drugs with anti-metastasis properties, including inhibitors of WNT signalling across various cancers.https://doi.org/10.1186/s12943-024-02182-wTranscription FactorsGene regulationSingle-cell heterogeneityMetastasisCancer |
| spellingShingle | Ryan Lusby Engin Demirdizen Mohammed Inayatullah Paramita Kundu Oscar Maiques Ziyi Zhang Mikkel Green Terp Victoria Sanz-Moreno Vijay K. Tiwari Pan-cancer drivers of metastasis Molecular Cancer Transcription Factors Gene regulation Single-cell heterogeneity Metastasis Cancer |
| title | Pan-cancer drivers of metastasis |
| title_full | Pan-cancer drivers of metastasis |
| title_fullStr | Pan-cancer drivers of metastasis |
| title_full_unstemmed | Pan-cancer drivers of metastasis |
| title_short | Pan-cancer drivers of metastasis |
| title_sort | pan cancer drivers of metastasis |
| topic | Transcription Factors Gene regulation Single-cell heterogeneity Metastasis Cancer |
| url | https://doi.org/10.1186/s12943-024-02182-w |
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