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Nat Cell Biol. 2018 Sep;20(9):1084-1097. doi: 10.1038/s41556-018-0173-5. Epub 2018 Aug 27.

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

Author information

1
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
2
Department of Medicine, Harvard Medical School, Boston, MA, USA.
3
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
4
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
5
Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Biostatistics, Harvard T.H. Chan, School of Public Health, Boston, MA, USA.
7
MIT Department of Biology and Ludwig/MIT Center for Molecular Oncology, Cambridge, MA, USA.
8
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. c.chaffer@garvan.org.au.
9
Whitehead Institute for Biomedical Research, Cambridge, MA, USA. c.chaffer@garvan.org.au.
10
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. smcallister1@bwh.harvard.edu.
11
Department of Medicine, Harvard Medical School, Boston, MA, USA. smcallister1@bwh.harvard.edu.
12
Broad Institute of Harvard and MIT, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.
13
Harvard Stem Cell Institute, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.

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-1β (IL-1β)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1β 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-1β 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.

PMID:
30154549
DOI:
10.1038/s41556-018-0173-5

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