Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development

Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (...
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Autor*in:	Mészáros, Ádám [verfasserIn] Molnár, Kinga Fazakas, Csilla Nógrádi, Bernát Lüvi, Adél Dudás, Tamás Tiszlavicz, László Farkas, Attila Elek Krizbai, István Adorján Wilhelm, Imola

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Brain metastasis IL-1β Inflammatory microenvironment NLRP3 inflammasome Peritumoral astrocytes Triple-negative breast cancer

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Acta Neuropathologica Communications - London : Biomed Central, 2013, 11(2023), 1 vom: 25. Sept.
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:1 ; day:25 ; month:09

Links:	Volltext

DOI / URN:	10.1186/s40478-023-01646-2

Katalog-ID:	SPR053196678

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allfields	10.1186/s40478-023-01646-2 doi (DE-627)SPR053196678 (SPR)s40478-023-01646-2-e DE-627 ger DE-627 rakwb eng Mészáros, Ádám verfasserin aut Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213 Molnár, Kinga aut Fazakas, Csilla aut Nógrádi, Bernát aut Lüvi, Adél aut Dudás, Tamás aut Tiszlavicz, László aut Farkas, Attila Elek aut Krizbai, István Adorján aut Wilhelm, Imola (orcid)0000-0003-2366-7337 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 25. Sept. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:25 month:09 https://dx.doi.org/10.1186/s40478-023-01646-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_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 11 2023 1 25 09
spelling	10.1186/s40478-023-01646-2 doi (DE-627)SPR053196678 (SPR)s40478-023-01646-2-e DE-627 ger DE-627 rakwb eng Mészáros, Ádám verfasserin aut Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213 Molnár, Kinga aut Fazakas, Csilla aut Nógrádi, Bernát aut Lüvi, Adél aut Dudás, Tamás aut Tiszlavicz, László aut Farkas, Attila Elek aut Krizbai, István Adorján aut Wilhelm, Imola (orcid)0000-0003-2366-7337 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 25. Sept. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:25 month:09 https://dx.doi.org/10.1186/s40478-023-01646-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_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 11 2023 1 25 09
allfields_unstemmed	10.1186/s40478-023-01646-2 doi (DE-627)SPR053196678 (SPR)s40478-023-01646-2-e DE-627 ger DE-627 rakwb eng Mészáros, Ádám verfasserin aut Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213 Molnár, Kinga aut Fazakas, Csilla aut Nógrádi, Bernát aut Lüvi, Adél aut Dudás, Tamás aut Tiszlavicz, László aut Farkas, Attila Elek aut Krizbai, István Adorján aut Wilhelm, Imola (orcid)0000-0003-2366-7337 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 25. Sept. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:25 month:09 https://dx.doi.org/10.1186/s40478-023-01646-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_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 11 2023 1 25 09
allfieldsGer	10.1186/s40478-023-01646-2 doi (DE-627)SPR053196678 (SPR)s40478-023-01646-2-e DE-627 ger DE-627 rakwb eng Mészáros, Ádám verfasserin aut Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213 Molnár, Kinga aut Fazakas, Csilla aut Nógrádi, Bernát aut Lüvi, Adél aut Dudás, Tamás aut Tiszlavicz, László aut Farkas, Attila Elek aut Krizbai, István Adorján aut Wilhelm, Imola (orcid)0000-0003-2366-7337 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 25. Sept. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:25 month:09 https://dx.doi.org/10.1186/s40478-023-01646-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_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 11 2023 1 25 09
allfieldsSound	10.1186/s40478-023-01646-2 doi (DE-627)SPR053196678 (SPR)s40478-023-01646-2-e DE-627 ger DE-627 rakwb eng Mészáros, Ádám verfasserin aut Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213 Molnár, Kinga aut Fazakas, Csilla aut Nógrádi, Bernát aut Lüvi, Adél aut Dudás, Tamás aut Tiszlavicz, László aut Farkas, Attila Elek aut Krizbai, István Adorján aut Wilhelm, Imola (orcid)0000-0003-2366-7337 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 25. Sept. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:25 month:09 https://dx.doi.org/10.1186/s40478-023-01646-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_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 11 2023 1 25 09
language	English
source	Enthalten in Acta Neuropathologica Communications 11(2023), 1 vom: 25. Sept. volume:11 year:2023 number:1 day:25 month:09
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topic_facet	Brain metastasis IL-1β Inflammatory microenvironment NLRP3 inflammasome Peritumoral astrocytes Triple-negative breast cancer
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author	Mészáros, Ádám
spellingShingle	Mészáros, Ádám misc Brain metastasis misc IL-1β misc Inflammatory microenvironment misc NLRP3 inflammasome misc Peritumoral astrocytes misc Triple-negative breast cancer Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
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topic_title	Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development Brain metastasis (dpeaa)DE-He213 IL-1β (dpeaa)DE-He213 Inflammatory microenvironment (dpeaa)DE-He213 NLRP3 inflammasome (dpeaa)DE-He213 Peritumoral astrocytes (dpeaa)DE-He213 Triple-negative breast cancer (dpeaa)DE-He213
topic	misc Brain metastasis misc IL-1β misc Inflammatory microenvironment misc NLRP3 inflammasome misc Peritumoral astrocytes misc Triple-negative breast cancer
topic_unstemmed	misc Brain metastasis misc IL-1β misc Inflammatory microenvironment misc NLRP3 inflammasome misc Peritumoral astrocytes misc Triple-negative breast cancer
topic_browse	misc Brain metastasis misc IL-1β misc Inflammatory microenvironment misc NLRP3 inflammasome misc Peritumoral astrocytes misc Triple-negative breast cancer
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title	Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
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title_full	Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
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author_browse	Mészáros, Ádám Molnár, Kinga Fazakas, Csilla Nógrádi, Bernát Lüvi, Adél Dudás, Tamás Tiszlavicz, László Farkas, Attila Elek Krizbai, István Adorján Wilhelm, Imola
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title_sort	inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
title_auth	Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
abstract	Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. © The Author(s) 2023
abstractGer	Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. © The Author(s) 2023
abstract_unstemmed	Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases. © The Author(s) 2023
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title_short	Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
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author2	Molnár, Kinga Fazakas, Csilla Nógrádi, Bernát Lüvi, Adél Dudás, Tamás Tiszlavicz, László Farkas, Attila Elek Krizbai, István Adorján Wilhelm, Imola
author2Str	Molnár, Kinga Fazakas, Csilla Nógrádi, Bernát Lüvi, Adél Dudás, Tamás Tiszlavicz, László Farkas, Attila Elek Krizbai, István Adorján Wilhelm, Imola
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up_date	2024-07-03T17:46:18.885Z
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By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. 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Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development

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