| Autor: |
Yakinthi Chrisochoidou, Rajat Roy, Pooyeh Farahmand, Guadalupe Gonzalez, Jennifer Doig, Lukas Krasny, Ella F. Rimmer, Anne E Willis, Marion MacFarlane, Paul H. Huang, Neil O. Carragher, Alison F. Munro, Daniel J. Murphy, Kirill Veselkov, Michael J. Seckl, Miriam F. Moffatt, William O. C. Cookson, Olivier E. Pardo |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 14, Iss 11, Pp 1-20 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-023-06240-x |
| Popis: |
Abstract Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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