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...
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| Autor*in: |
Menga, Alessio [verfasserIn] Serra, Marina [verfasserIn] Todisco, Simona [verfasserIn] Riera‐Domingo, Carla [verfasserIn] Ammarah, Ummi [verfasserIn] Ehling, Manuel [verfasserIn] Palmieri, Erika M [verfasserIn] Di Noia, Maria Antonietta [verfasserIn] Gissi, Rosanna [verfasserIn] Favia, Maria [verfasserIn] Pierri, Ciro L [verfasserIn] Porporato, Paolo E [verfasserIn] Castegna, Alessandra [verfasserIn] Mazzone, Massimiliano [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 12(2020), 10 vom: 04. Sept. |
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| Übergeordnetes Werk: |
volume:12 ; year:2020 ; number:10 ; day:04 ; month:09 |
| Links: |
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| DOI / URN: |
10.15252/emmm.201911210 |
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| Katalog-ID: |
SPR058030441 |
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| 245 | 1 | 0 | |a Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
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| 520 | |a 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. | ||
| 520 | |a Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. | ||
| 520 | |a Graphical Abstract 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. | ||
| 650 | 4 | |a glufosinate |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Serra, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Todisco, Simona |e verfasserin |4 aut | |
| 700 | 1 | |a Riera‐Domingo, Carla |e verfasserin |4 aut | |
| 700 | 1 | |a Ammarah, Ummi |e verfasserin |4 aut | |
| 700 | 1 | |a Ehling, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Palmieri, Erika M |e verfasserin |4 aut | |
| 700 | 1 | |a Di Noia, Maria Antonietta |e verfasserin |4 aut | |
| 700 | 1 | |a Gissi, Rosanna |e verfasserin |4 aut | |
| 700 | 1 | |a Favia, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Pierri, Ciro L |e verfasserin |4 aut | |
| 700 | 1 | |a Porporato, Paolo E |e verfasserin |4 aut | |
| 700 | 1 | |a Castegna, Alessandra |e verfasserin |0 (orcid)0000-0003-0235-6847 |4 aut | |
| 700 | 1 | |a Mazzone, Massimiliano |e verfasserin |0 (orcid)0000-0001-8824-4015 |4 aut | |
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10.15252/emmm.201911210 doi (DE-627)SPR058030441 (SPR)emmm.201911210-e DE-627 ger DE-627 rakwb eng Menga, Alessio verfasserin (orcid)0000-0002-2827-5298 aut Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 Serra, Marina verfasserin aut Todisco, Simona verfasserin aut Riera‐Domingo, Carla verfasserin aut Ammarah, Ummi verfasserin aut Ehling, Manuel verfasserin aut Palmieri, Erika M verfasserin aut Di Noia, Maria Antonietta verfasserin aut Gissi, Rosanna verfasserin aut Favia, Maria verfasserin aut Pierri, Ciro L verfasserin aut Porporato, Paolo E verfasserin aut Castegna, Alessandra verfasserin (orcid)0000-0003-0235-6847 aut Mazzone, Massimiliano verfasserin (orcid)0000-0001-8824-4015 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 12(2020), 10 vom: 04. Sept. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:12 year:2020 number:10 day:04 month:09 https://dx.doi.org/10.15252/emmm.201911210 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 12 2020 10 04 09 |
| spelling |
10.15252/emmm.201911210 doi (DE-627)SPR058030441 (SPR)emmm.201911210-e DE-627 ger DE-627 rakwb eng Menga, Alessio verfasserin (orcid)0000-0002-2827-5298 aut Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 Serra, Marina verfasserin aut Todisco, Simona verfasserin aut Riera‐Domingo, Carla verfasserin aut Ammarah, Ummi verfasserin aut Ehling, Manuel verfasserin aut Palmieri, Erika M verfasserin aut Di Noia, Maria Antonietta verfasserin aut Gissi, Rosanna verfasserin aut Favia, Maria verfasserin aut Pierri, Ciro L verfasserin aut Porporato, Paolo E verfasserin aut Castegna, Alessandra verfasserin (orcid)0000-0003-0235-6847 aut Mazzone, Massimiliano verfasserin (orcid)0000-0001-8824-4015 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 12(2020), 10 vom: 04. Sept. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:12 year:2020 number:10 day:04 month:09 https://dx.doi.org/10.15252/emmm.201911210 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 12 2020 10 04 09 |
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10.15252/emmm.201911210 doi (DE-627)SPR058030441 (SPR)emmm.201911210-e DE-627 ger DE-627 rakwb eng Menga, Alessio verfasserin (orcid)0000-0002-2827-5298 aut Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 Serra, Marina verfasserin aut Todisco, Simona verfasserin aut Riera‐Domingo, Carla verfasserin aut Ammarah, Ummi verfasserin aut Ehling, Manuel verfasserin aut Palmieri, Erika M verfasserin aut Di Noia, Maria Antonietta verfasserin aut Gissi, Rosanna verfasserin aut Favia, Maria verfasserin aut Pierri, Ciro L verfasserin aut Porporato, Paolo E verfasserin aut Castegna, Alessandra verfasserin (orcid)0000-0003-0235-6847 aut Mazzone, Massimiliano verfasserin (orcid)0000-0001-8824-4015 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 12(2020), 10 vom: 04. Sept. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:12 year:2020 number:10 day:04 month:09 https://dx.doi.org/10.15252/emmm.201911210 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 12 2020 10 04 09 |
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10.15252/emmm.201911210 doi (DE-627)SPR058030441 (SPR)emmm.201911210-e DE-627 ger DE-627 rakwb eng Menga, Alessio verfasserin (orcid)0000-0002-2827-5298 aut Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 Serra, Marina verfasserin aut Todisco, Simona verfasserin aut Riera‐Domingo, Carla verfasserin aut Ammarah, Ummi verfasserin aut Ehling, Manuel verfasserin aut Palmieri, Erika M verfasserin aut Di Noia, Maria Antonietta verfasserin aut Gissi, Rosanna verfasserin aut Favia, Maria verfasserin aut Pierri, Ciro L verfasserin aut Porporato, Paolo E verfasserin aut Castegna, Alessandra verfasserin (orcid)0000-0003-0235-6847 aut Mazzone, Massimiliano verfasserin (orcid)0000-0001-8824-4015 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 12(2020), 10 vom: 04. Sept. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:12 year:2020 number:10 day:04 month:09 https://dx.doi.org/10.15252/emmm.201911210 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 12 2020 10 04 09 |
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10.15252/emmm.201911210 doi (DE-627)SPR058030441 (SPR)emmm.201911210-e DE-627 ger DE-627 rakwb eng Menga, Alessio verfasserin (orcid)0000-0002-2827-5298 aut Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 Serra, Marina verfasserin aut Todisco, Simona verfasserin aut Riera‐Domingo, Carla verfasserin aut Ammarah, Ummi verfasserin aut Ehling, Manuel verfasserin aut Palmieri, Erika M verfasserin aut Di Noia, Maria Antonietta verfasserin aut Gissi, Rosanna verfasserin aut Favia, Maria verfasserin aut Pierri, Ciro L verfasserin aut Porporato, Paolo E verfasserin aut Castegna, Alessandra verfasserin (orcid)0000-0003-0235-6847 aut Mazzone, Massimiliano verfasserin (orcid)0000-0001-8824-4015 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 12(2020), 10 vom: 04. Sept. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:12 year:2020 number:10 day:04 month:09 https://dx.doi.org/10.15252/emmm.201911210 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 12 2020 10 04 09 |
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Enthalten in EMBO Molecular Medicine 12(2020), 10 vom: 04. Sept. volume:12 year:2020 number:10 day:04 month:09 |
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Enthalten in EMBO Molecular Medicine 12(2020), 10 vom: 04. Sept. volume:12 year:2020 number:10 day:04 month:09 |
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Menga, Alessio @@aut@@ Serra, Marina @@aut@@ Todisco, Simona @@aut@@ Riera‐Domingo, Carla @@aut@@ Ammarah, Ummi @@aut@@ Ehling, Manuel @@aut@@ Palmieri, Erika M @@aut@@ Di Noia, Maria Antonietta @@aut@@ Gissi, Rosanna @@aut@@ Favia, Maria @@aut@@ Pierri, Ciro L @@aut@@ Porporato, Paolo E @@aut@@ Castegna, Alessandra @@aut@@ Mazzone, Massimiliano @@aut@@ |
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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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract The GS inhibitor glufosinate is shown to significantly reduce metachronous and synchronous metastasis with no detectable toxicity. 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Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages glufosinate (dpeaa)DE-He213 glutamine synthetase (dpeaa)DE-He213 immunometabolism (dpeaa)DE-He213 macrophages (dpeaa)DE-He213 metastasis (dpeaa)DE-He213 |
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Menga, Alessio Serra, Marina Todisco, Simona Riera‐Domingo, Carla Ammarah, Ummi Ehling, Manuel Palmieri, Erika M Di Noia, Maria Antonietta Gissi, Rosanna Favia, Maria Pierri, Ciro L Porporato, Paolo E Castegna, Alessandra Mazzone, Massimiliano |
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glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| title_auth |
Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
| abstract |
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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. © The Author(s) 2020 |
| abstractGer |
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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. © The Author(s) 2020 |
| abstract_unstemmed |
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. Synopsis 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. Glutamine synthetase expression is a typical feature of “M2‐like” macrophages and tumor‐associated macrophages (TAMs), and its pharmacological targeting with glufosinate elicits therapeutic effects in murine models of highly metastatic melanoma, breast and lung cancer.Upon treatment with glufosinate in tumor‐bearing mice, TAMs are reprogrammed from a protumoral to an antitumoral phenotype, as evidenced by changes in molecular markers and biological functions.Treatment of tumor‐bearing mice with glufosinate stimulates cytotoxic T cells while decreasing vessel sprouting, leading to reduction of metachronous and synchronous metastasis through TAM reprogramming.Therapeutic doses of glufosinate do not display overt signs of brain, liver, kidney, or hematological toxicities. Graphical Abstract 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. © The Author(s) 2020 |
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Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages |
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Serra, Marina Todisco, Simona Riera‐Domingo, Carla Ammarah, Ummi Ehling, Manuel Palmieri, Erika M Di Noia, Maria Antonietta Gissi, Rosanna Favia, Maria Pierri, Ciro L Porporato, Paolo E Castegna, Alessandra Mazzone, Massimiliano |
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| score |
7.4024754 |