Microenvironmental IL1 1 β promotes metastatic colonisation of breast cancer cells in the bone via activation of Wnt-dependent cancer stem cell activity

Rachel Eyre, Denis G Alférez, Angélica Santiago-Gómez, Kath Spence, James C McConnell, Claire Hart, Bruno M Simões, Claudia Tulotta, Joanna Storer, Austin Gurney, Noel Clarke, Michael D Brown, Sacha J Howell, Andrew Sims, Gillian Farnie, Penelope D Ottewell, Robert B. Clarke

Research output: Contribution to journalArticlepeer-review

Abstract

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before clinical bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the growth of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are the cells capable of metastasis, but the mechanism by which disseminated CSCs colonise the bone is unknown. Here, we establish that normal bone marrow derived factors promote the ability of CSCs to form metastatic colonies. These include IL1β, which has previously been proposed as a metastasis driver, but a lack of clear mechanism has limited the use of inhibitors clinically. Here, we establish that microenvironmental IL1β stimulates metastatic breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, which leads to autocrine Wnt signalling and CSC activity. Importantly, we show that inhibition of the IL1β-NFKB/CREB-Wnt pathway at critical points prevents both CSC colony formation in the bone environment, and bone metastasis in vivo. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy in breast cancer to prevent clinical bone metastasis.
Original languageEnglish
JournalNature Communications
Early online date1 Nov 2019
DOIs
Publication statusE-pub ahead of print - 1 Nov 2019

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