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Tissue-Resident Alveolar Macrophages Control the Timing of Breast Cancer Metastatic Outgrowth in the Lung

Dalla, E;Papanicolaou, M;Park, M;Hou, R;Sun, D;Forrest, A;Barth, N;Casanova-Acebes, M;Entenberg, D;Merad, M;Aguirre-Ghiso, J;

Breast disseminated cancer cells (DCCs) can lodge in the lungs early during cancer evolution and persist dormant for long periods. However, how lung niches limit multi-focal DCC expansion is unclear. Using single-cell RNA-sequencing and intravital imaging, we uncover reciprocal regulation between homeostatic, tissue-resident alveolar macrophages (AMs) and breast cancer DCCs within the alveoli. Ligand-receptor mapping and intravital imaging revealed that AMs produce pro-dormancy TGF-b1/2 and oncostatin-M that keep breast DCCs in a Ki67-/ZEB1hi/ZFP281hi/SNAILhi/CDH1lo mesenchymal-like dormant state. In turn, DCCs instruct AMs to reduce pro-inflammatory TLR and LPS signaling. Depletion of AMs resulted in metastatic outbreak by dormant DCCs re-entering the cell cycle and increased the infiltration of inflammatory and immunosuppressive cells. Metastatic outgrowth correlated with loss of tissue homeostasis due to the accumulation of CXCL16+ pro-inflammatory AMs in the lung. We reveal that AMs serve as a barrier to breast cancer lung metastasis, which might be exploited for anti-metastatic therapies.