Abstract A59: Macrophages orchestrate early dissemination of HER2+ cancer cells

Abstract

Abstract Metastatic dissemination can already occur during early pre-invasive breast cancer stages. However mechanisms that control early cancer cell dissemination are unclear. Here we show that MMTV-HER2 early cancer lesions contain an invasive subpopulation of HER2+/E-cadherinlo cancer cells that disseminate by recruiting resident CD206+ mammary tissue resident macrophages (MTMs). This occurs months before monocyte-derived macrophages are recruited into advanced tumors. Early HER2+ lesions, but not healthy mammary tissue, produced CCL2 in an NFκB dependent manner and recruited intra-ductal MTMs, that secreted Wnt1 and thereby induced an epithelial to mesenchymal transition (EMT) in the early HER2+ cancer cells. Depletion of MTMs before overt tumors appeared prevented early cancer cells from undergoing an EMT and drastically reduced early dissemination. Surprisingly macrophage depleting therapy in MMTV-Her2 only during pre-malignant stages reduced alveolar metastases, even when mice went through invasive tumor stages and macrophages had repopulated the overt tumor tissue. Importantly, humans with DCIS lesions that contained macrophage+/E-Cadherinlo microenvironments frequently had disseminated cancer cell (DCCs) in the bone marrow. Taken together, we reveal that resident MTMs 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. Citation Format: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Sosa, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio Aguirre-Ghiso. Macrophages orchestrate early dissemination of HER2+ cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A59.