NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis

Nour Ershaid, Yoray Sharon, Hila Doron, Yael Raz, Ophir Shani, Noam Cohen, Lea Monteran, Leonor Leider-Trejo, Amir Ben-Shmuel, Muhammad Yassin, Motti Gerlic, Adit Ben-Baruch, Metsada Pasmanik-Chor, Roni Apte, Neta Erez

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Cancer-Associated Fibroblasts (CAFs) were shown to orchestrate tumour-promoting inflammation in multiple malignancies, including breast cancer. However, the molecular pathways that govern the inflammatory role of CAFs are poorly characterised. In this study we found that fibroblasts sense damage-associated molecular patterns (DAMPs), and in response activate the NLRP3 inflammasome pathway, resulting in instigation of pro-inflammatory signalling and secretion of IL-1β. This upregulation was evident in CAFs in mouse and in human breast carcinomas. Moreover, CAF-derived inflammasome signalling facilitated tumour growth and metastasis, which was attenuated when NLRP3 or IL-1β were specifically ablated. Functionally, CAF-derived inflammasome promoted tumour progression and metastasis by modulating the tumour microenvironment towards an immune suppressive milieu and by upregulating the expression of adhesion molecules on endothelial cells. Our findings elucidate a mechanism by which CAFs promote breast cancer progression and metastasis, by linking the physiological tissue damage response of fibroblasts with tumour-promoting inflammation.

Original languageEnglish
Article number4375
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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