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IL-1beta inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization

Abstract

Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1beta (IL-1beta)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1beta maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1beta expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival.

Type Journal
ISBN 1465-7392
Authors Castano, Z.; San Juan, B. P.; Spiegel, A.; Pant, A.; DeCristo, M. J.; Laszewski, T.; Ubellacker, J. M.; Janssen, S. R.; Dongre, A.; Reinhardt, F.; Henderson, A.; Del Rio, A. G.; Gifford, A. M.; Herbert, Z. T.; Hutchinson, J. N.; Weinberg, R. A.; Chaffer, C. L.; McAllister, S. S.
Responsible Garvan Author Dr Christine Chaffer
Publisher Name NATURE CELL BIOLOGY
Published Date 2018-09-01
Published Volume 20
Published Issue 9
Published Pages 1084-1097
Status Published in-print
DOI 10.1038/s41556-018-0173-5
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/?term=30154549