Project description:Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM 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 cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells. Methods: Meso-CAFs were isolated from surgical specimens of MPM patients and analyzed by comparative genomic hybridization, transcriptomics and proteomics. Human MPM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, and response to pathway inhibitors and cisplatin was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results: Meso-CAFs possess normal genomes without gene copy number aberrations typical for MPM cells. They express CAF markers and lack MPM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in the fraction of actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in increased proliferation and migration of MPM cells. A similar effect on cell growth was induced by conditioned medium. Met/PI3K or WNT signaling inhibition abolished the Meso-CAF-mediated growth stimulation. While Meso-CAFs reduced the efficacy of EGFR inhibition in co-cultures, they did not provide protection of tumor cells against cisplatin. Conclusion: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on tumor cell growth and migration, two key aspects of MPM aggressiveness, indicating a substantial role of Meso-CAFs in driving MPM progression. Moreover, we show that Meso-CAFs significantly influence drug response and identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for improving therapeutic strategies in MPM.

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SLC13A5 plays an essential role in the energy shift to oxidative phosphorylation in cisplatin-resistant mesothelioma stem cells

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