Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.
Date
2023-11-08ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Mice
Humans
Mesothelioma, Malignant
Mesothelioma
Fibroblasts
Cancer-Associated Fibroblasts
Lung
Research team
Mol and Systems Oncology
Language
eng
Date accepted
2023-10-20
License start date
2023-11-08
Citation
Cell Death and Disease, 2023, 14 (11), pp. 725 -
Publisher
SPRINGERNATURE