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

ABSTRACT: Global gene expression of spontaneous breast tumors developed in transgenic mice at different time course (FVB/N-MMTV-PyMT: model of spontaneous mammary carcinoma. Lin EY et al.,Am J Pathol. 2003 Nov;163(5):2113-26. Cancer-Associated Fibroblasts (CAFs) are highly abundant in the microenvironment of breast tumors. CAFs were shown to orchestrate tumor-promoting inflammation in multiple malignancies, including breast cancer. However, the molecular pathways that govern the inflammatory role of CAFs are poorly characterized. In this study we found that fibroblasts can sense damage-associated molecular patterns (DAMPs), and in response activate the NLRP3 inflammasome pathway, resulting in instigation of pro-inflammatory signaling and secretion of IL-1β. This upregulation was evident in CAFs in mouse and in human breast carcinomas. Moreover, CAF-derived inflammasome signaling facilitated mammary tumor growth and lung metastasis, which was attenuated when NLRP3 or IL-1β were specifically ablated. Functionally, CAF-derived inflammasome promoted tumor progression and metastasis by modulating the tumor microenvironment towards an immune suppressive milieu and by upregulating the expression of adhesion molecules on endothelial cells. Thus, our findings elucidate a novel mechanism by which CAFs promote breast cancer progression and lung metastasis, by linking the physiological tissue damage response of fibroblasts with tumor-promoting inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE129189 | GEO | 2019/09/02

REPOSITORIES: GEO

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