Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.
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Embargo End Date
ICR Authors
Authors
Chrisochoidou, Y
Roy, R
Farahmand, P
Gonzalez, G
Doig, J
Krasny, L
Rimmer, EF
Willis, AE
MacFarlane, M
Huang, PH
Carragher, NO
Munro, AF
Murphy, DJ
Veselkov, K
Seckl, MJ
Moffatt, MF
Cookson, WOC
Pardo, OE
Roy, R
Farahmand, P
Gonzalez, G
Doig, J
Krasny, L
Rimmer, EF
Willis, AE
MacFarlane, M
Huang, PH
Carragher, NO
Munro, AF
Murphy, DJ
Veselkov, K
Seckl, MJ
Moffatt, MF
Cookson, WOC
Pardo, OE
Document Type
Journal Article
Date
2023-11-08
Date Accepted
2023-10-20
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.
Citation
Cell Death and Disease, 2023, 14 (11), pp. 725 -
Source Title
Cell Death and Disease
Publisher
SPRINGERNATURE
ISSN
2041-4889
eISSN
2041-4889
2041-4889
2041-4889
Collections
Research Team
Mol and Systems Oncology