IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.
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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. |
Year of Publication | 2018
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Journal | Nat Cell Biol
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Volume | 20
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Issue | 9
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Pages | 1084-1097
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Date Published | 2018 09
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ISSN | 1476-4679
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DOI | 10.1038/s41556-018-0173-5
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PubMed ID | 30154549
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PubMed Central ID | PMC6511979
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Grant list | R01 CA166284 / CA / NCI NIH HHS / United States
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