Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer

• Published in: Cell reports (Cambridge) Vol. 27; no. 7; pp. 1967 - 1978.e4
• Main Authors: Evans, Rachel, Flores-Borja, Fabian, Nassiri, Sina, Miranda, Elena, Lawler, Katherine, Grigoriadis, Anita, Monypenny, James, Gillet, Cheryl, Owen, Julie, Gordon, Peter, Male, Victoria, Cheung, Anthony, Noor, Farzana, Barber, Paul, Marlow, Rebecca, Francesch-Domenech, Erika, Fruhwirth, Gilbert, Squadrito, Mario, Vojnovic, Borivoj, Tutt, Andrew, Festy, Frederic, De Palma, Michele, Ng, Tony
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-05-2019; Cell Press; Elsevier
• Subjects: adhesion; Animals; cancer; Cell Adhesion - genetics; Cell Adhesion Molecules - metabolism; contraction; Endothelial Cells - metabolism; Female; Gene Expression Regulation, Neoplastic - genetics; HEK293 Cells; Humans; Integrin beta4 - genetics; Integrin beta4 - metabolism; Kalinin; Lymphatic Metastasis; Lymphatic Vessels - cytology; Lymphatic Vessels - metabolism; Lymphatic Vessels - pathology; lymphovasculature; macrophages; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; remodeling; RhoA; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Signal Transduction - genetics; TGF-β1; 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; β4 integrin; macrophages; remodeling; β4 integrin; contraction; TGF-β1; cancer; adhesion; RhoA; lymphovasculature
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.076

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.
[Display omitted]
•β4 integrin-expressing macrophages release TGF-β1 near breast cancer lymphovasculature•TGF-β1 drives β4 integrin clustering on macrophages, enhancing macrophage adhesion•TGF-β1 signals through RhoA to drive to lymphatic endothelial cell contraction•Lymphatic remodeling signaling cascade facilitates breast cancer metastasis
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.