Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling
Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression...
Ausführliche Beschreibung
Autor*in: |
Wang, Shengqi [verfasserIn] Li, Jing [verfasserIn] Hong, Shicui [verfasserIn] Wang, Neng [verfasserIn] Xu, Shang [verfasserIn] Yang, Bowen [verfasserIn] Zheng, Yifeng [verfasserIn] Zhang, Juping [verfasserIn] Pan, Bo [verfasserIn] Hu, Yudie [verfasserIn] Wang, Zhiyu [verfasserIn] |
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E-Artikel |
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Englisch |
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2024 |
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Anmerkung: |
© The Author(s) 2024 |
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Übergeordnetes Werk: |
Enthalten in: Journal of experimental & clinical cancer research - BioMed Central, 2008, 43(2024), 1 vom: 23. Apr. |
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Übergeordnetes Werk: |
volume:43 ; year:2024 ; number:1 ; day:23 ; month:04 |
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DOI / URN: |
10.1186/s13046-024-03050-7 |
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Katalog-ID: |
SPR055620817 |
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520 | |a Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract | ||
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10.1186/s13046-024-03050-7 doi (DE-627)SPR055620817 (SPR)s13046-024-03050-7-e DE-627 ger DE-627 rakwb eng 610 VZ Wang, Shengqi verfasserin aut Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract TNBC (dpeaa)DE-He213 Dying cell (dpeaa)DE-He213 Extracellular vesicle (dpeaa)DE-He213 CXCL1 (dpeaa)DE-He213 Tumor-associated macrophage (dpeaa)DE-He213 PD-L1 (dpeaa)DE-He213 Li, Jing verfasserin aut Hong, Shicui verfasserin aut Wang, Neng verfasserin aut Xu, Shang verfasserin aut Yang, Bowen verfasserin aut Zheng, Yifeng verfasserin aut Zhang, Juping verfasserin aut Pan, Bo verfasserin aut Hu, Yudie verfasserin aut Wang, Zhiyu verfasserin (orcid)0000-0002-5299-8410 aut Enthalten in Journal of experimental & clinical cancer research BioMed Central, 2008 43(2024), 1 vom: 23. Apr. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:43 year:2024 number:1 day:23 month:04 https://dx.doi.org/10.1186/s13046-024-03050-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 1 23 04 |
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10.1186/s13046-024-03050-7 doi (DE-627)SPR055620817 (SPR)s13046-024-03050-7-e DE-627 ger DE-627 rakwb eng 610 VZ Wang, Shengqi verfasserin aut Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract TNBC (dpeaa)DE-He213 Dying cell (dpeaa)DE-He213 Extracellular vesicle (dpeaa)DE-He213 CXCL1 (dpeaa)DE-He213 Tumor-associated macrophage (dpeaa)DE-He213 PD-L1 (dpeaa)DE-He213 Li, Jing verfasserin aut Hong, Shicui verfasserin aut Wang, Neng verfasserin aut Xu, Shang verfasserin aut Yang, Bowen verfasserin aut Zheng, Yifeng verfasserin aut Zhang, Juping verfasserin aut Pan, Bo verfasserin aut Hu, Yudie verfasserin aut Wang, Zhiyu verfasserin (orcid)0000-0002-5299-8410 aut Enthalten in Journal of experimental & clinical cancer research BioMed Central, 2008 43(2024), 1 vom: 23. Apr. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:43 year:2024 number:1 day:23 month:04 https://dx.doi.org/10.1186/s13046-024-03050-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 1 23 04 |
allfields_unstemmed |
10.1186/s13046-024-03050-7 doi (DE-627)SPR055620817 (SPR)s13046-024-03050-7-e DE-627 ger DE-627 rakwb eng 610 VZ Wang, Shengqi verfasserin aut Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract TNBC (dpeaa)DE-He213 Dying cell (dpeaa)DE-He213 Extracellular vesicle (dpeaa)DE-He213 CXCL1 (dpeaa)DE-He213 Tumor-associated macrophage (dpeaa)DE-He213 PD-L1 (dpeaa)DE-He213 Li, Jing verfasserin aut Hong, Shicui verfasserin aut Wang, Neng verfasserin aut Xu, Shang verfasserin aut Yang, Bowen verfasserin aut Zheng, Yifeng verfasserin aut Zhang, Juping verfasserin aut Pan, Bo verfasserin aut Hu, Yudie verfasserin aut Wang, Zhiyu verfasserin (orcid)0000-0002-5299-8410 aut Enthalten in Journal of experimental & clinical cancer research BioMed Central, 2008 43(2024), 1 vom: 23. Apr. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:43 year:2024 number:1 day:23 month:04 https://dx.doi.org/10.1186/s13046-024-03050-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 1 23 04 |
allfieldsGer |
10.1186/s13046-024-03050-7 doi (DE-627)SPR055620817 (SPR)s13046-024-03050-7-e DE-627 ger DE-627 rakwb eng 610 VZ Wang, Shengqi verfasserin aut Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract TNBC (dpeaa)DE-He213 Dying cell (dpeaa)DE-He213 Extracellular vesicle (dpeaa)DE-He213 CXCL1 (dpeaa)DE-He213 Tumor-associated macrophage (dpeaa)DE-He213 PD-L1 (dpeaa)DE-He213 Li, Jing verfasserin aut Hong, Shicui verfasserin aut Wang, Neng verfasserin aut Xu, Shang verfasserin aut Yang, Bowen verfasserin aut Zheng, Yifeng verfasserin aut Zhang, Juping verfasserin aut Pan, Bo verfasserin aut Hu, Yudie verfasserin aut Wang, Zhiyu verfasserin (orcid)0000-0002-5299-8410 aut Enthalten in Journal of experimental & clinical cancer research BioMed Central, 2008 43(2024), 1 vom: 23. Apr. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:43 year:2024 number:1 day:23 month:04 https://dx.doi.org/10.1186/s13046-024-03050-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 1 23 04 |
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10.1186/s13046-024-03050-7 doi (DE-627)SPR055620817 (SPR)s13046-024-03050-7-e DE-627 ger DE-627 rakwb eng 610 VZ Wang, Shengqi verfasserin aut Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract TNBC (dpeaa)DE-He213 Dying cell (dpeaa)DE-He213 Extracellular vesicle (dpeaa)DE-He213 CXCL1 (dpeaa)DE-He213 Tumor-associated macrophage (dpeaa)DE-He213 PD-L1 (dpeaa)DE-He213 Li, Jing verfasserin aut Hong, Shicui verfasserin aut Wang, Neng verfasserin aut Xu, Shang verfasserin aut Yang, Bowen verfasserin aut Zheng, Yifeng verfasserin aut Zhang, Juping verfasserin aut Pan, Bo verfasserin aut Hu, Yudie verfasserin aut Wang, Zhiyu verfasserin (orcid)0000-0002-5299-8410 aut Enthalten in Journal of experimental & clinical cancer research BioMed Central, 2008 43(2024), 1 vom: 23. Apr. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:43 year:2024 number:1 day:23 month:04 https://dx.doi.org/10.1186/s13046-024-03050-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 1 23 04 |
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chemotherapy-elicited extracellular vesicle cxcl1 from dying cells promotes triple-negative breast cancer metastasis by activating tam/pd-l1 signaling |
title_auth |
Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling |
abstract |
Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract © The Author(s) 2024 |
abstractGer |
Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract © The Author(s) 2024 |
abstract_unstemmed |
Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that $ CXCL1^{EV-dead} $ enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight $ CXCL1^{EV-dead} $ as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract © The Author(s) 2024 |
collection_details |
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container_issue |
1 |
title_short |
Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling |
url |
https://dx.doi.org/10.1186/s13046-024-03050-7 |
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Li, Jing Hong, Shicui Wang, Neng Xu, Shang Yang, Bowen Zheng, Yifeng Zhang, Juping Pan, Bo Hu, Yudie Wang, Zhiyu |
author2Str |
Li, Jing Hong, Shicui Wang, Neng Xu, Shang Yang, Bowen Zheng, Yifeng Zhang, Juping Pan, Bo Hu, Yudie Wang, Zhiyu |
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up_date |
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Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-$ L1^{+} $ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. 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