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 S. Condeelis, Miriam Merad, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 number2481
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

macrophages
Macrophages
metastasis
breast
cancer
Breast Neoplasms
Neoplasm Metastasis
Cells
Neoplasms
Cadherins
progressions
lesions
Carcinoma, Intraductal, Noninfiltrating
Tumor Microenvironment
Myeloid Cells
Tumors
Up-Regulation
Down-Regulation
mice
depletion

ASJC Scopus subject areas

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

Cite this

Linde, N., Casanova-Acebes, M., Sosa, M. S., Mortha, A., Rahman, A., Farias, E., ... Aguirre-Ghiso, J. A. (2018). Macrophages orchestrate breast cancer early dissemination and metastasis. Nature Communications, 9(1), [2481]. https://doi.org/10.1038/s41467-017-02481-5

Macrophages orchestrate breast cancer early dissemination and metastasis. / 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 S.; Merad, Miriam; Aguirre-Ghiso, Julio A.

In: Nature Communications, Vol. 9, No. 1, 2481, 01.12.2018.

Research output: Contribution to journalArticle

Linde, N, Casanova-Acebes, M, Sosa, MS, Mortha, A, Rahman, A, Farias, E, Harper, K, Tardio, E, Reyes Torres, I, Jones, J, Condeelis, JS, Merad, M & Aguirre-Ghiso, JA 2018, 'Macrophages orchestrate breast cancer early dissemination and metastasis', Nature Communications, vol. 9, no. 1, 2481. https://doi.org/10.1038/s41467-017-02481-5
Linde N, Casanova-Acebes M, Sosa MS, Mortha A, Rahman A, Farias E et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nature Communications. 2018 Dec 1;9(1). 2481. https://doi.org/10.1038/s41467-017-02481-5
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 S. ; Merad, Miriam ; Aguirre-Ghiso, Julio A. / Macrophages orchestrate breast cancer early dissemination and metastasis. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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