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LYVE-1-expressing macrophages modulate the extracellular matrix in the mammary gland and contribute to mammary tumor growth

ABSTRACT: Macrophages represent a heterogeneous myeloid population with diverse functions in normal tissues and tumors. While LYVE-1 macrophages have been identified in stromal regions of the normal mammary gland and mammary tumor, their functions in these regions remain unknown. Using a genetic LYVE-1+ macrophage deletion model, we demonstrate that loss of LYVE-1+ macrophages leads to accumulation of the extracellular matrix glycosaminoglycan hyaluronan. Consistent with this finding, we demonstrate that LYVE-1 expression correlates with an increased ability of macrophages to bind, internalize, and degrade hyaluronan. Furthermore, we demonstrate that deletion of LYVE-1+ macrophages results in increased hyaluronan accumulation in mammary tumors, which correlates with reduced tumor growth. Finally, using scRNA-seq, we demonstrate that deletion of LYVE-1 macrophages in tumors results in a shift in the remaining macrophages towards a pro-inflammatory phenotype. Together, these findings demonstrate that LYVE-1+ macrophages represent an anti-inflammatory macrophage population that contributes to tissue remodeling in the tumor microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE241469 | GEO | 2024/06/05

REPOSITORIES: GEO

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Resident macrophages promote homeostasis of hyaluronan-associated extracellular matrix in the mammary gland stroma

Project description:Tissue resident macrophages in the mammary gland are found in close association with epithelial structures and within the adipose stroma, and are important for mammary gland development and tissue homeostasis. While epithelial-associated macrophages have been linked to ductal development, the contributions of stromal macrophages to mammary gland homeostasis remain unknown. Using transcriptional profiling, we identify a distinct resident stromal macrophage subpopulation that is characterized by expression of Lyve-1, a receptor for the extracellular matrix component hyaluronan. This subpopulation is enriched in genes associated with extracellular matrix remodeling and is found to be specifically associated with hyaluronan-rich regions within the mammary stroma. Furthermore, macrophage depletion leads to increased accumulation of hyaluronan-associated extracellular matrix in the mammary stroma. These results demonstrate the presence of a distinct subpopulation of macrophages and provide insights into the functional contributions of these macrophages to stromal homeostasis in the mammary gland.

2020-05-31 | GSE148207 | GEO

Lyve-1 deficiency plasma proteomics

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2023-03-11 | PXD032717 | Pride

Distinct lactation-associated macrophages exist in murine mammary tissue and human milk

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2024-07-16 | GSE225295 | GEO

Profiling of murine resident adipose tissue and aortic macrophages according to their expression status of LYVE-1

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2018-06-01 | GSE114630 | GEO

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Project description:Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the pro-tumorigenic factor cyclooxygenase-2 (COX-2) and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a novel mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

2019-05-16 | GSE131300 | GEO

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