A Positive Feedback Loop between Mesenchymal-like Cancer Cells and Macrophages Is Essential to Breast Cancer Metastasis

• Cancer cells with EMT activate macrophages to a TAM-like phenotype by GM-CSF
• TAMs induce EMT of breast cancer cells via CCL18 to form a positive feedback loop
• The interaction between cancer cells with EMT and TAMs is essential to metastasis
• High GM-CSF or CCL18 in cancer samples is associated with EMT and poor prognosis

SummaryThe close vicinity of cancer cells undergoing epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) at the invasive front of tumors suggests that these two cell type may mutually interact. We show that mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype by GM-CSF. Reciprocally, CCL18 from TAMs induces cancer cell EMT, forming a positive feedback loop, in coculture systems and humanized mice. Inhibition of GM-CSF or CCL18 breaks this loop and reduces cancer metastasis. High GM-CSF expression in breast cancer samples is associated with more CCL18+ macrophages, cancer cell EMT, enhanced metastasis, and reduced patient survival. These findings suggest that a positive feedback loop between GM-CSF and CCL18 is important in breast cancer metastasis.

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