CXCL12-CXCR4 signaling mediates the formation of a macrophageal niche for mammary tumorigenesis [tumor]

Niche-associated signals, essential for the maintenance of normal stem cells and tumor-initiating cells, are spatially confined and exert their influence locally among adjacent cells. Here, we demonstrate that CXCR4+ macrophages are enriched in the normal mammary ducts and enhance regenerative activity in basal cells in response to the CXCL12 secreted by luminal cells. Conditional knockout of CXCR4 in macrophages or CXCL12 in luminal cells results in similar phenotypes, including impaired branching morphogenesis, decreased regenerative functionality in basal cells, and diminished ductal association of macrophages. CXCL12 stimulation of macrophages triggers an AKT-mediated stabilization of β-catenin, increasing the expression of pro-migratory genes and multiple Wnt ligands, which enhances the infiltration of macrophages and their ability to support stem-like regenerative functions of basal cells. Importantly, the identical CXCR4+ niche macrophages also govern the tumor-initiating activity of breast tumors by promoting the survival and tumor-forming capacity of tumor-initiating cells and inducing early immune evasion through the accumulation of regulatory T cells. Our findings elucidate a crucial role of the CXCL12-CXCR4 axis in facilitating a complex interaction among niche macrophages, two mammary epithelial cell lineages, and other stromal components, thereby establishing a supportive environment for both normal tissue regeneration and mammary tumor initiation.