Complexity of progranulin mechanisms of action in mesothelioma
Abstract Background Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02546-4 |
| _version_ | 1828092591405531136 |
|---|---|
| author | Elisa Ventura Christopher Xie Simone Buraschi Antonino Belfiore Renato V. Iozzo Antonio Giordano Andrea Morrione |
| author_facet | Elisa Ventura Christopher Xie Simone Buraschi Antonino Belfiore Renato V. Iozzo Antonio Giordano Andrea Morrione |
| author_sort | Elisa Ventura |
| collection | DOAJ |
| description | Abstract Background Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells. Methods The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers. Results In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility. Conclusion Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease. |
| first_indexed | 2024-04-11T06:31:07Z |
| format | Article |
| id | doaj.art-e08f6f96642a486a9f7e6d7ebb919edd |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T06:31:07Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e08f6f96642a486a9f7e6d7ebb919edd2022-12-22T04:40:05ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-12-0141112110.1186/s13046-022-02546-4Complexity of progranulin mechanisms of action in mesotheliomaElisa Ventura0Christopher Xie1Simone Buraschi2Antonino Belfiore3Renato V. Iozzo4Antonio Giordano5Andrea Morrione6Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple UniversityDepartment of Pathology, Anatomy and Cell Biology, Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson UniversityDepartment of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima HospitalDepartment of Pathology, Anatomy and Cell Biology, Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson UniversitySbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple UniversitySbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple UniversityAbstract Background Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells. Methods The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers. Results In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility. Conclusion Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease.https://doi.org/10.1186/s13046-022-02546-4MesotheliomaProgranulinEphA2EGFRRYKFAK |
| spellingShingle | Elisa Ventura Christopher Xie Simone Buraschi Antonino Belfiore Renato V. Iozzo Antonio Giordano Andrea Morrione Complexity of progranulin mechanisms of action in mesothelioma Journal of Experimental & Clinical Cancer Research Mesothelioma Progranulin EphA2 EGFR RYK FAK |
| title | Complexity of progranulin mechanisms of action in mesothelioma |
| title_full | Complexity of progranulin mechanisms of action in mesothelioma |
| title_fullStr | Complexity of progranulin mechanisms of action in mesothelioma |
| title_full_unstemmed | Complexity of progranulin mechanisms of action in mesothelioma |
| title_short | Complexity of progranulin mechanisms of action in mesothelioma |
| title_sort | complexity of progranulin mechanisms of action in mesothelioma |
| topic | Mesothelioma Progranulin EphA2 EGFR RYK FAK |
| url | https://doi.org/10.1186/s13046-022-02546-4 |
| work_keys_str_mv | AT elisaventura complexityofprogranulinmechanismsofactioninmesothelioma AT christopherxie complexityofprogranulinmechanismsofactioninmesothelioma AT simoneburaschi complexityofprogranulinmechanismsofactioninmesothelioma AT antoninobelfiore complexityofprogranulinmechanismsofactioninmesothelioma AT renatoviozzo complexityofprogranulinmechanismsofactioninmesothelioma AT antoniogiordano complexityofprogranulinmechanismsofactioninmesothelioma AT andreamorrione complexityofprogranulinmechanismsofactioninmesothelioma |