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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE275907 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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

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