Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer

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