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

Our plain-English summary of Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells, by Y. Chrisochoidou, R. Roy, P. Farahmand, et al (Cell Death & Disease, 2023).

The study

• Authors: Y. Chrisochoidou, R. Roy, P. Farahmand, G. Gonzalez, J. Doig, L. Krasny, E.F. Rimmer, A.E. Willis, M. MacFarlane, P.H. Huang, N.O. Carragher, A.F. Munro, D.J. Murphy, K. Veselkov, M.J. Seckl, M.F. Moffatt, W.O.C. Cookson, O.E. Pardo
• Journal: Cell Death & Disease
• Published: 2023;14(11):725
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2023. The Author(s).

In plain English

This was a laboratory study of how mesothelioma cells and lung fibroblasts influence each other. The authors cultured patient-derived pleural mesothelioma cell lines (Meso 8, 12, 23, 27, 33, 60 and 70), the immortalised mesothelial line Met-5A, and MRC-5 human lung fibroblasts, alone, in conditioned media and as 3D co-culture spheroids. Conditioned media from all seven mesothelioma lines attracted MRC-5 fibroblasts within 24 hours and raised activation markers (FAP, alpha-smooth muscle actin, fibronectin), which media from Met-5A cells did not. Media from these activated fibroblasts in turn attracted and activated further naive fibroblasts. The cisplatin/pemetrexed combination was significantly less effective (p less than 0.0001) in fibroblast/mesothelioma co-cultures than in mesothelioma spheroids alone, and fibroblast-derived extracellular matrix reduced its efficacy further. Among drugs tested, vistusertib alone, and combinations with cediranib or saracatinib, outperformed cisplatin/pemetrexed in co-cultures. In asbestos (amosite)-exposed Nf2/Bap1/Cdkn2a triple-floxed mice, saracatinib alone improved median survival by 72 days (p less than 0.05).

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory study combining in vitro co-cultures of cell lines with an in vivo genetically-engineered mouse experiment
• Who was studied: Patient-derived pleural mesothelioma cell lines (Meso 8, 12, 23, 27, 33, 60, 70), the mesothelial line Met-5A, commercial lines NCI-H2052 and MSTO-211H, MRC-5 human lung fibroblasts; plus Nf2/Bap1/Cdkn2a triple-floxed mice (minimum 6 mice per treatment arm)
• Exposure: Fibroblasts and tumour cells exposed to each other's conditioned media and extracellular matrix; drugs tested at 10 µM (TRC105 at 50 µM); mice given a single intrapleural injection of 25 µg amosite asbestos fibres
• Main results:
  • Conditioned media from all seven mesothelioma cell lines attracted MRC-5 lung fibroblasts within 24 hours
  • Fibroblasts exposed to mesothelioma cell media showed activation markers, which did not occur with Met-5A media
  • Activated fibroblasts themselves attracted and activated naive fibroblasts, more quickly than mesothelioma cells did (significant recruitment at 6 hours)
  • In mesothelioma cells, cisplatin/pemetrexed was significantly less effective when activated fibroblasts were present in the spheroid
  • Matrix made by activated fibroblasts further reduced cisplatin/pemetrexed efficacy in all co-cultures
  • Of the single agents tested in co-cultures, only the mTOR inhibitor vistusertib beat cisplatin/pemetrexed
  • Two drug pairs outperformed standard-of-care in malignant co-cultures with limited toxicity on mesothelial cell cultures
  • In asbestos-exposed mice, saracatinib alone extended median survival by 72 days and beat cisplatin/pemetrexed; vistusertib alone did not help and the combination was toxic
• The authors' conclusion: The authors concluded that they identified signalling crosstalk between mesothelioma cells and activated fibroblasts that can be targeted, and that drug combinations against it were more effective in vitro than current standard-of-care, with further research needed before clinical translation.
• Limitations the authors state:
  • The authors noted they may have had too few cell lines to detect links between fibroblast behaviour and mesothelioma genetic background or subtype
  • The authors flagged the toxicity of the saracatinib plus vistusertib combination in their mouse model
  • The authors stated further research is needed on clinical translation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Fibroblast, Mesothelioma, Prognosis, Cisplatin, Pemetrexed (Alimta), Overall Survival.

Related studies

• Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells — T. Chernova, S. Grosso, et al. (2022)
• Fibroblast-like cells in mesothelioma can derive from tumor cells — J.M. Garcia-Manteiga, E. Rrapaj, et al. (2026)
• Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma — Y. Ohara, A. Enomoto, et al. (2020)
• Cancer-Associated Fibroblasts Regulate Kinase Activity in Mesothelioma Cell Lines via Paracrine Signaling and Thereby Dictate Cell Faith and Behavior — A. Mathilakathu, M. Wessolly, et al. (2022)
• A comparison of the cytogenetic response to asbestos and glass fibre in Chinese hamster and human cell lines. Demonstration of growth inhibition in primary human fibroblasts — A.M. Sincock, J.D. Delhanty, et al. (1982)
• BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients — M. De Marco, N. Del Papa, et al. (2022)

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