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

Author:

Mészáros Ádám,Molnár Kinga,Fazakas Csilla,Nógrádi Bernát,Lüvi Adél,Dudás Tamás,Tiszlavicz László,Farkas Attila Elek,Krizbai István Adorján,Wilhelm ImolaORCID

Abstract

AbstractInflammasomes, 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.

Funder

Nemzeti Kutatási Fejlesztési és Innovációs Hivatal

Magyar Tudományos Akadémia

Eötvös Loránd Research Network

Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii

Innovációs és Technológiai Minisztérium

Richter Gedeon Talentum Alapítvány

ELKH Biological Research Center

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine

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