Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin
Abstract Background Pleural 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02582-0 |
| _version_ | 1811175666138218496 |
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| author | Alexander Ries Daniela Flehberger Astrid Slany Christine Pirker Johanna C. Mader Thomas Mohr Karin Schelch Katharina Sinn Berta Mosleh Mir Alireza Hoda Balazs Dome Helmut Dolznig Georg Krupitza Leonhard Müllauer Christopher Gerner Walter Berger Michael Grusch |
| author_facet | Alexander Ries Daniela Flehberger Astrid Slany Christine Pirker Johanna C. Mader Thomas Mohr Karin Schelch Katharina Sinn Berta Mosleh Mir Alireza Hoda Balazs Dome Helmut Dolznig Georg Krupitza Leonhard Müllauer Christopher Gerner Walter Berger Michael Grusch |
| author_sort | Alexander Ries |
| collection | DOAJ |
| description | Abstract Background Pleural 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. Methods Meso-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. Results Meso-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. Conclusions Our 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. |
| first_indexed | 2024-04-10T19:39:25Z |
| format | Article |
| id | doaj.art-0584feb1baa7455e98b30e32f6b10aef |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-10T19:39:25Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-0584feb1baa7455e98b30e32f6b10aef2023-01-29T12:24:40ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-01-0142112010.1186/s13046-022-02582-0Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatinAlexander Ries0Daniela Flehberger1Astrid Slany2Christine Pirker3Johanna C. Mader4Thomas Mohr5Karin Schelch6Katharina Sinn7Berta Mosleh8Mir Alireza Hoda9Balazs Dome10Helmut Dolznig11Georg Krupitza12Leonhard Müllauer13Christopher Gerner14Walter Berger15Michael Grusch16Center for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaDepartment of Analytical Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaDepartment of Analytical Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Medical University of ViennaDepartment of Thoracic Surgery, Medical University of ViennaDepartment of Thoracic Surgery, Medical University of ViennaDepartment of Thoracic Surgery, Medical University of ViennaInstitute of Medical Genetics, Medical University of ViennaDepartment of Clinical Pathology, Medical University of ViennaDepartment of Clinical Pathology, Medical University of ViennaDepartment of Analytical Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaAbstract Background Pleural 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. Methods Meso-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. Results Meso-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. Conclusions Our 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.https://doi.org/10.1186/s13046-022-02582-0Pleural mesotheliomaCancer-associated fibroblastsCo-culturesTumor microenvironmentWNTPI3K |
| spellingShingle | Alexander Ries Daniela Flehberger Astrid Slany Christine Pirker Johanna C. Mader Thomas Mohr Karin Schelch Katharina Sinn Berta Mosleh Mir Alireza Hoda Balazs Dome Helmut Dolznig Georg Krupitza Leonhard Müllauer Christopher Gerner Walter Berger Michael Grusch 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 Pleural mesothelioma Cancer-associated fibroblasts Co-cultures Tumor microenvironment WNT PI3K |
| title | Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin |
| title_full | Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin |
| title_fullStr | Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin |
| title_full_unstemmed | Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin |
| title_short | Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin |
| title_sort | mesothelioma associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c met pi3k and wnt signaling but do not protect against cisplatin |
| topic | Pleural mesothelioma Cancer-associated fibroblasts Co-cultures Tumor microenvironment WNT PI3K |
| url | https://doi.org/10.1186/s13046-022-02582-0 |
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