Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

Journal of Experimental & Clinical Cancer Research

Research

Alexander Ries¹  Walter Berger¹  Christine Pirker¹  Michael Grusch¹  Daniela Flehberger¹  Thomas Mohr²  Karin Schelch³  Astrid Slany⁴  Christopher Gerner⁴  Johanna C. Mader⁴  Georg Krupitza⁵  Leonhard Müllauer⁵  Mir Alireza Hoda⁶  Berta Mosleh⁶  Katharina Sinn⁶  Balazs Dome⁷  Helmut Dolznig⁸ 

[1] Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria;Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria;Department of Analytical Chemistry, University of Vienna, Waehringer Straße 38, 1090, Vienna, Austria;Joint Metabolome Facility, University of Vienna and Medical University of Vienna, Waehringer Guertel 38, 1090, Vienna, Austria;ScienceConsult - DI Thomas Mohr KG, Enzianweg 10a, 2353, Guntramsdorf, Austria;Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria;Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria;Department of Analytical Chemistry, University of Vienna, Waehringer Straße 38, 1090, Vienna, Austria;Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria;Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria;Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria;National Korányi Institute of Pulmonology, Korányi Frigyes u. 1, 1122, Budapest, Hungary;Department of Thoracic Surgery, National Institute of Oncology, Semmelweis University, Rath Gyorgy u. 7-9, 1122, Budapest, Hungary;Institute of Medical Genetics, Medical University of Vienna, Waehringer Straße 10, 1090, Vienna, Austria;

关键词: Pleural mesothelioma;    Cancer-associated fibroblasts;    Co-cultures;    Tumor microenvironment;    WNT;    PI3K;    C-Met;    HGF;    Cisplatin;    Pemetrexed;   

DOI  :  10.1186/s13046-022-02582-0

 received in 2022-09-08, accepted in 2022-12-24,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundPleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells.MethodsMeso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis.ResultsMeso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib.ConclusionsOur study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.

【 授权许可】

CC BY   
© The Author(s) 2023

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