Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages
Abstract Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2‐like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the for...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201911210 |
| _version_ | 1827015190377398272 |
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| author | Alessio Menga Marina Serra Simona Todisco Carla Riera‐Domingo Ummi Ammarah Manuel Ehling Erika M Palmieri Maria Antonietta Di Noia Rosanna Gissi Maria Favia Ciro L Pierri Paolo E Porporato Alessandra Castegna Massimiliano Mazzone |
| author_facet | Alessio Menga Marina Serra Simona Todisco Carla Riera‐Domingo Ummi Ammarah Manuel Ehling Erika M Palmieri Maria Antonietta Di Noia Rosanna Gissi Maria Favia Ciro L Pierri Paolo E Porporato Alessandra Castegna Massimiliano Mazzone |
| author_sort | Alessio Menga |
| collection | DOAJ |
| description | Abstract Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2‐like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti‐tumor, M1‐like, tumor‐associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1‐like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well‐tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis. |
| first_indexed | 2024-03-07T17:33:47Z |
| format | Article |
| id | doaj.art-2172c31045fb4eb88d755d43558791aa |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:34Z |
| publishDate | 2020-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2172c31045fb4eb88d755d43558791aa2024-10-28T08:55:08ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-09-01121012410.15252/emmm.201911210Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophagesAlessio Menga0Marina Serra1Simona Todisco2Carla Riera‐Domingo3Ummi Ammarah4Manuel Ehling5Erika M Palmieri6Maria Antonietta Di Noia7Rosanna Gissi8Maria Favia9Ciro L Pierri10Paolo E Porporato11Alessandra Castegna12Massimiliano Mazzone13Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIBLaboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIBDepartment of Sciences, University of BasilicataLaboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIBDepartment of Molecular Biotechnology and Health Science, Molecular Biotechnology Centre, University of TorinoLaboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIBCancer & Inflammation Program, National Cancer InstituteDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of BariDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of BariDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of BariDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of BariDepartment of Molecular Biotechnology and Health Science, Molecular Biotechnology Centre, University of TorinoDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of BariLaboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIBAbstract Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2‐like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti‐tumor, M1‐like, tumor‐associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1‐like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well‐tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis.https://doi.org/10.15252/emmm.201911210glufosinateglutamine synthetaseimmunometabolismmacrophagesmetastasis |
| spellingShingle | Alessio Menga Marina Serra Simona Todisco Carla Riera‐Domingo Ummi Ammarah Manuel Ehling Erika M Palmieri Maria Antonietta Di Noia Rosanna Gissi Maria Favia Ciro L Pierri Paolo E Porporato Alessandra Castegna Massimiliano Mazzone Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages EMBO Molecular Medicine glufosinate glutamine synthetase immunometabolism macrophages metastasis |
| title | Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_full | Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_fullStr | Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_full_unstemmed | Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_short | Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_sort | glufosinate constrains synchronous and metachronous metastasis by promoting anti tumor macrophages |
| topic | glufosinate glutamine synthetase immunometabolism macrophages metastasis |
| url | https://doi.org/10.15252/emmm.201911210 |
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