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Cancer research communications
May 31, 2024;4 (5): 1380-1397.

LYVE-1-expressing Macrophages Modulate the Hyaluronan-containing Extracellular Matrix in the Mammary Stroma and Contribute to Mammary Tumor Growth.

Alexis K Elfstrum, Annisa H Rumahorbo, Lyndsay E Reese, Emma V Nelson, Braedan M McCluskey, Kathryn L Schwertfeger
Author Information
  1. Alexis K Elfstrum: Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota. ORCID
  2. Annisa H Rumahorbo: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. ORCID
  3. Lyndsay E Reese: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. ORCID
  4. Emma V Nelson: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. ORCID
  5. Braedan M McCluskey: University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota. ORCID
  6. Kathryn L Schwertfeger: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. ORCID
PMID: 38717149 DOI: 10.1158/2767-9764.CRC-24-0205

Abstract

Macrophages represent a heterogeneous myeloid population with diverse functions in normal tissues and tumors. While macrophages expressing the cell surface marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) have been identified in stromal regions of the normal mammary gland and in the peritumoral stroma, their functions within these regions are not well understood. Using a genetic mouse model of LYVE-1+ macrophage depletion, we demonstrate that loss of LYVE-1+ macrophages is associated with altered extracellular matrix remodeling in the normal mammary gland and reduced mammary tumor growth in vivo. In further studies focused on investigating the functions of LYVE-1+ macrophages in the tumor microenvironment, we demonstrate that LYVE-1 expression correlates with an increased ability of macrophages to bind, internalize, and degrade hyaluronan. Consistent with this, we show that depletion of LYVE-1+ macrophages correlates with increased hyaluronan accumulation in both the normal mammary gland and in mammary tumors. Analysis of single-cell RNA sequencing of macrophages isolated from these tumors reveals that depletion of LYVE-1+ macrophages in tumors drives a shift in the majority of the remaining macrophages toward a proinflammatory phenotype, as well as an increase in CD8+ T-cell infiltration. Together, these findings indicate that LYVE-1+ macrophages represent a tumor-promoting anti-inflammatory subset of macrophages that contributes to hyaluronan remodeling in the tumor microenvironment.
SIGNIFICANCE: We have identified a macrophage subset in mouse mammary tumors associated with tumor structural components. When this macrophage subset is absent in tumors, we report a delay in tumor growth and an increase in antitumor immune cells. Understanding the functions of distinct macrophage subsets may allow for improved therapeutic strategies for patients with breast cancer.

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Grants

  1. T32 AI007313/NIAID NIH HHS
  2. R01HD106929/HHS | National Institutes of Health (NIH)
  3. R01 CA265004/NCI NIH HHS
  4. R01HD95858/HHS | National Institutes of Health (NIH)
  5. R01 HD106929/NICHD NIH HHS
  6. R01 HD095858/NICHD NIH HHS
  7. R01CA215052/HHS | National Institutes of Health (NIH)
  8. R01 CA215052/NCI NIH HHS
  9. R01CA265004/HHS | National Institutes of Health (NIH)
  10. UL1 TR002494/NCATS NIH HHS
  11. T32AI007313/HHS | National Institutes of Health (NIH)

MeSH Term

Animals
Female
Mice
Breast Neoplasms
Extracellular Matrix
Hyaluronic Acid
Macrophages
Mammary Glands, Animal
Mammary Neoplasms, Experimental
Stromal Cells
Tumor Microenvironment
Vesicular Transport Proteins

Chemicals

Hyaluronic Acid
LYVE1 protein, mouse
Vesicular Transport Proteins
Journal Article
Article has an altmetric score of 3

Word Cloud

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