Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer

Cell Rep. 2019 May 14;27(7):1967-1978.e4. doi: 10.1016/j.celrep.2019.04.076.

Abstract

Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in β4 integrin-dependent adhesion to the lymphovasculature. β4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-β1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-β1 drives β4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-β1 signaling in this context. β4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-β signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between β4 integrin and TGF-β1.

Keywords: RhoA; TGF-β1; adhesion; cancer; contraction; lymphovasculature; macrophages; remodeling; β4 integrin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / genetics
  • Cell Adhesion Molecules / metabolism
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Humans
  • Integrin beta4 / genetics
  • Integrin beta4 / metabolism*
  • Lymphatic Metastasis
  • Lymphatic Vessels / cytology*
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / pathology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Signal Transduction / genetics
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Cell Adhesion Molecules
  • Integrin beta4
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • kalinin
  • RHOA protein, human
  • rhoA GTP-Binding Protein