Macrophages orchestrate breast cancer early dissemination and metastasis

• Published in: Nature communications Vol. 9; no. 1; p. 21
• Main Authors: Linde, Nina, Casanova-Acebes, Maria, Sosa, Maria Soledad, Mortha, Arthur, Rahman, Adeeb, Farias, Eduardo, Harper, Kathryn, Tardio, Ethan, Reyes Torres, Ivan, Jones, Joan, Condeelis, John, Merad, Miriam, Aguirre-Ghiso, Julio A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.01.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 14; 14/63; 42; 42/44; 631/67/1347; 631/67/322; 631/67/327; 631/67/580; 64; 64/60; 96; 96/21; Animals; Breast cancer; Breast Neoplasms - pathology; Cancer; Disease Progression; E-cadherin; ErbB-2 protein; Female; Humanities and Social Sciences; Lesions; Macrophages; Macrophages - pathology; Metastases; Metastasis; Mice; Microenvironments; Monocyte chemoattractant protein 1; multidisciplinary; Myeloid cells; Neoplasm Metastasis; RAW 264.7 Cells; Receptor, ErbB-2 - genetics; Science; Science (multidisciplinary); Wnt protein; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02481-5

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. Early dissemination of cancer cells has been reported to occur in certain breast cancer models. Here the authors show that intra-epithelial macrophages in the early pre-cancer lesions drive early cancer cell dissemination through Wnt-1 secretion and that such events impact the later development of metastasis.