Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells
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 cel...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06240-x |
| _version_ | 1797629972159922176 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yakinthi Chrisochoidou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:00:24Z |
| format | Article |
| id | doaj.art-aaf6d7ac3e1a4d1b86de96ee85ac0b92 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T11:00:24Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-aaf6d7ac3e1a4d1b86de96ee85ac0b922023-11-12T12:31:26ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141112010.1038/s41419-023-06240-xCrosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cellsYakinthi Chrisochoidou0Rajat Roy1Pooyeh Farahmand2Guadalupe Gonzalez3Jennifer Doig4Lukas Krasny5Ella F. Rimmer6Anne E Willis7Marion MacFarlane8Paul H. Huang9Neil O. Carragher10Alison F. Munro11Daniel J. Murphy12Kirill Veselkov13Michael J. Seckl14Miriam F. Moffatt15William O. C. Cookson16Olivier E. Pardo17Division of Cancer, Imperial CollegeDivision of Cancer, Imperial CollegeInstitute of Cancer Sciences, University of GlasgowDepartment of Computing, Faculty of Engineering, Imperial College LondonInstitute of Cancer Sciences, University of GlasgowMolecular and Systems Oncology, The Institute of Cancer ResearchDivision of Cancer, Imperial CollegeMRC Toxicology UnitMRC Toxicology UnitMolecular and Systems Oncology, The Institute of Cancer ResearchCancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghCancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghInstitute of Cancer Sciences, University of GlasgowDivision of Cancer, Imperial CollegeDivision of Cancer, Imperial CollegeNational Heart and Lung Institute, Imperial CollegeNational Heart and Lung Institute, Imperial CollegeDivision of Cancer, Imperial CollegeAbstract 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.https://doi.org/10.1038/s41419-023-06240-x |
| spellingShingle | 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 Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells Cell Death and Disease |
| title | Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| title_full | Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| title_fullStr | Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| title_full_unstemmed | Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| title_short | Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| title_sort | crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells |
| url | https://doi.org/10.1038/s41419-023-06240-x |
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