Macrophages orchestrate breast cancer early dissemination and metastasis

Nina Linde, Maria Casanova-Acebes, Maria Soledad Sosa, Arthur Mortha, Adeeb Rahman, Eduardo Farias, Kathryn Harper, Ethan Tardio, Ivan Reyes Torres, Joan Jones, John Condeelis, Miriam Merad and Julio A. Aguirre-Ghiso ()
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Nina Linde: Icahn School of Medicine at Mount Sinai
Maria Casanova-Acebes: Icahn School of Medicine at Mount Sinai
Maria Soledad Sosa: Icahn School of Medicine at Mount Sinai
Arthur Mortha: Icahn School of Medicine at Mount Sinai
Adeeb Rahman: Icahn School of Medicine at Mount Sinai
Eduardo Farias: Icahn School of Medicine at Mount Sinai
Kathryn Harper: Icahn School of Medicine at Mount Sinai
Ethan Tardio: Icahn School of Medicine at Mount Sinai
Ivan Reyes Torres: Icahn School of Medicine at Mount Sinai
Joan Jones: Albert Einstein College of Medicine
John Condeelis: Albert Einstein College of Medicine
Miriam Merad: Icahn School of Medicine at Mount Sinai
Julio A. Aguirre-Ghiso: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.

Date: 2018
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DOI: 10.1038/s41467-017-02481-5

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