Identifying actionable pathways in breast cancer serosal metastasis
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Embargo End Date
2027-10-10
ICR Authors
Authors
Skiadas, G
Document Type
Thesis or Dissertation
Date
2025-10-10
Date Accepted
Abstract
Metastasis to the peritoneal and pleural cavities, also termed the serous cavities, is a common occurrence in advanced breast cancer. The serous cavities are lined by the mesothelium, an epithelial monolayer which provides a hospitable environment for the serosal spread of intra-abdominal cancers. Despite breast cancer being the most common extra-abdominal cancer spreading to the serosal cavities and the leading cause of pleural effusion and ascites in women, patients with breast cancer serosal metastasis face limited therapeutic options. The aim of this project was to uncover the mechanisms of crosstalk between mesothelial cells and breast cancer cells and to reveal therapeutic vulnerabilities that impair serosal colonisation.Using a novel ultrasound-guided intrapleural injection model and an intraperitoneal injection model, I showed that breast cancer cells co-localise with mesothelial cells and rapidly expand along the sub-mesothelial basal lamina when inoculated in the serous cavities. Furthermore, breast cancer cells co-cultured with mesothelial cells as 3D spheroids show increased viability compared to tumour cells alone, and loss of E-cadherin in tumour cells potentiates this interaction. Transcriptomic analysis and cell-cell communication inference of the co-cultured spheroids pinpointed basement membrane components as top predicted mesothelial-derived ligands binding to tumour cell receptors. In parallel, mesothelial cells acquired a cancer-associated mesothelial cell signature upon co-culture with tumour cells, displaying increased extracellular matrix (ECM) deposition and remodelling. Validation of top communication inference candidate genes by RNA interference identified mesothelial-derived fibronectin and laminin α5 as ECM components involved in the regulation of tumour cell viability. Targeting tumour cell binding of the mesothelial basement membrane via FAK inhibition is being tested as a strategy to limit serosal spread of breast cancer in vivo. Together these results demonstrate that mesothelial cells provide a supportive niche for breast cancer serosal colonisation and that mesothelial-tumour cell interaction is an actionable target against advanced metastatic disease.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Molecular Cell Biology