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Macrophage Function in Early Dissemination and Dormancy of Breast Cancer

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Technical Report,01 Sep 2014,31 Aug 2015

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Icahn School of Medicine at Mount Sinai New York United States

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This research project focuses on the role of macrophages in early dissemination and dormancy. We hypothesized that macrophages are actively recruited by pre-malignant ErbB2 overexpressing cancer cells and that these intra-epithelial macrophages then produce factors that induce an EMT and thereby facilitate early dissemination. We further hypothesized that bone marrow but not lung macrophages produce TGFb2, BMP7 and other factors that instruct DCCs to enter dormancy. In this report we now provide evidence that early ErbB2 lesions, but not healthy mammary tissue, produced CCL2 in an NFkB dependent manner and recruited intra-ductal macrophages, that secrete Wnt1 and thereby induce an EMT in the early ErbB2 cancer cells. Depletion of macrophages, but only before overt advanced tumors appeared, drastically reduced early dissemination and surprisingly the onset of metastasis even after macrophages repopulated the overt tumor tissue. Importantly, humans with DCIS lesions, a very early stage of breast cancer, that contained macrophageE-Cadherinlo microenvironments frequently had disseminated cancer cell DCCs in the bone marrow. We reveal that resident macrophages can promote early dissemination explaining how early cancer spread might proceed in breast cancer patients. We also propose that eDCCs play a long-term causal role in metastasis development.

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