Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages
| Autor: | Alessandra Castegna, Maria Antonietta Di Noia, Rosanna Gissi, Alessio Menga, Carla Riera-Domingo, Manuel Ehling, Marina Serra, Maria Favia, Ciro Leonardo Pierri, Ummi Ammarah, Erika M. Palmieri, Massimiliano Mazzone, Simona Todisco, Paolo E. Porporato |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Medicine (General) immunometabolism Breast Neoplasms glufosinate QH426-470 Biology Article Metastasis Mice 03 medical and health sciences chemistry.chemical_compound R5-920 0302 clinical medicine Glutamine synthetase Chemical Biology Genetics medicine Animals Humans metastasis Cancer Aminobutyrates Macrophages Intravasation glutamine synthetase macrophages Articles medicine.disease Primary tumor Extravasation 3. Good health Interleukin 10 Metabolism 030104 developmental biology Glufosinate chemistry Cancer cell Cancer research Molecular Medicine Female Inflammation Mediators 030217 neurology & neurosurgery |
| Zdroj: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 12, Iss 10, Pp n/a-n/a (2020) |
| ISSN: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.201911210 |
| Popis: | 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. The GS inhibitor glufosinate is shown to significantly reduce metachronous and synchronous metastasis with no detectable toxicity. This occurs by selective rewiring of both TAMs and MAMs to an antitumoral function, reducing immunosuppression and angiogenesis with a consequent decrease of metastasis. |
| Databáze: | OpenAIRE |
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