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Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells
- Source :
- Cell Death and Disease, Vol 14, Iss 11, Pp 1-20 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Publishing Group, 2023.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 14
- Issue :
- 11
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Death and Disease
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.f6d7ac3e1a4d1b86de96ee85ac0b92
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41419-023-06240-x