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, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticle

95 Scopus citations

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.

Original languageEnglish (US)
Article number21
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Linde, N., Casanova-Acebes, M., Sosa, M. S., Mortha, A., Rahman, A., Farias, E., Harper, K., Tardio, E., Reyes Torres, I., Jones, J., Condeelis, J., Merad, M., & Aguirre-Ghiso, J. A. (2018). Macrophages orchestrate breast cancer early dissemination and metastasis. Nature communications, 9(1), [21]. https://doi.org/10.1038/s41467-017-02481-5