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 and Neta Erez ()
Additional contact information
Nour Ershaid: Tel Aviv University
Yoray Sharon: Tel Aviv University
Hila Doron: Tel Aviv University
Yael Raz: Tel Aviv University
Ophir Shani: Tel Aviv University
Noam Cohen: Tel Aviv University
Lea Monteran: Tel Aviv University
Leonor Leider-Trejo: Tel Aviv University
Amir Ben-Shmuel: Israel Institute for Biological Research
Muhammad Yassin: Tel Aviv University
Motti Gerlic: Tel Aviv University
Adit Ben-Baruch: Tel Aviv University
Metsada Pasmanik-Chor: Tel Aviv University
Roni Apte: Ben Gurion University of the Negev
Neta Erez: Tel Aviv University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12370-8

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