Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells

Cell Death and Disease 2023 November 8 [Link]

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


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.