Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer

Summary: 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. : Breast cancer metastasis through lymphatic vessels is associated with poor prognosis. Evans et al. describe β4 integrin-expressing macrophages that regulate lymphatic vessel structure in breast cancer. Macrophage-released TGF-β1 drives lymphatic cell contraction via RhoA activation, culminating in lymphatic hyperpermeability. This study defines a signaling cascade that could be targeted therapeutically. Keywords: lymphovasculature, macrophages, cancer, remodeling, adhesion, contraction, β4 integrin, TGF-β1, RhoA