Dataset Information

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 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Fibroblast

DISEASE(S): Asbestos-related Lung Carcinoma

SUBMITTER: Madhumeeta Chadha

LAB HEAD: Paul Huang

PROVIDER: PXD040492 | Pride | 2024-01-26

REPOSITORIES: Pride

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			Action	DRS
	20181123_AP_Lukas_TMT_QE_rep1.raw	Raw
	20181123_AP_Lukas_TMT_QE_rep2.raw	Raw
	20181123_AP_Lukas_TMT_QE_rep3.raw	Raw
	proteinGroups.txt	Txt

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

Chrisochoidou Yakinthi Y Roy Rajat R Farahmand Pooyeh P Gonzalez Guadalupe G Doig Jennifer J Krasny Lukas L Rimmer Ella F EF Willis Anne E AE MacFarlane Marion M Huang Paul H PH Carragher Neil O NO Munro Alison F AF Murphy Daniel J DJ Veselkov Kirill K Seckl Michael J MJ Moffatt Miriam F MF Cookson William O C WOC Pardo Olivier E OE

Cell death & disease 20231108 11

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 pro ...[more]

PMID: 37938546

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Project description:Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts, the IL-1β ligand in CCR2 monocytes and macrophages, and inhibited IL-1β signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1β and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.