Journal
EMBO MOLECULAR MEDICINE
Volume 12, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201911210
Keywords
glufosinate; glutamine synthetase; immunometabolism; macrophages; metastasis
Categories
Funding
- ERC Consolidator Grant (ImmunoFit) [773208]
- FWO [G0D1717N, G066515N]
- Stichting Tegen Kanker [2014-197]
- Italian Ministry of Economic Development (MISE) [F/200076/01-02/X45]
- AIRC [MFAG 21564]
- EMBO
- FEBS Fellowship
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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.
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