Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling

Rachel Eyre, Denis G. Alférez, Angélica Santiago-Gómez, Kath Spence, James C. McConnell, Claire Hart, Bruno M. Simões, Diane Lefley, Claudia Tulotta, Joanna Storer, Austin Gurney, Noel Clarke, Mick Brown, Sacha J. Howell, Andrew H. Sims, Gillian Farnie, Penelope D. Ottewell () and Robert B. Clarke ()
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Rachel Eyre: University of Manchester
Denis G. Alférez: University of Manchester
Angélica Santiago-Gómez: University of Manchester
Kath Spence: University of Manchester
James C. McConnell: University of Manchester
Claire Hart: University of Manchester
Bruno M. Simões: University of Manchester
Diane Lefley: University of Sheffield
Claudia Tulotta: University of Sheffield
Joanna Storer: University of Manchester
Austin Gurney: OncoMed Pharmaceuticals
Noel Clarke: Salford Royal Hospital NHS Foundation Trust, Stott Lane
Mick Brown: University of Manchester
Sacha J. Howell: University of Manchester
Andrew H. Sims: University of Edinburgh
Gillian Farnie: Structural Genomics Consortium, NDORMS, Botnar Research Centre
Penelope D. Ottewell: University of Sheffield
Robert B. Clarke: University of Manchester

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

Abstract: 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 bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

Date: 2019
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DOI: 10.1038/s41467-019-12807-0

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