Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer.

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 ?4 integrin-dependent adhesion to the lymphovasculature. ?4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-?1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-?1 drives ?4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-?1 signaling in this context. ?4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-? signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between ?4 integrin and TGF-?1.

SUBMITTER: Evans R 

PROVIDER: S-EPMC6527923 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature