1. Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer.
- Author
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Evans R, Flores-Borja F, Nassiri S, Miranda E, Lawler K, Grigoriadis A, Monypenny J, Gillet C, Owen J, Gordon P, Male V, Cheung A, Noor F, Barber P, Marlow R, Francesch-Domenech E, Fruhwirth G, Squadrito M, Vojnovic B, Tutt A, Festy F, De Palma M, and Ng T
- Subjects
- Animals, Cell Adhesion genetics, Cell Adhesion Molecules metabolism, Endothelial Cells metabolism, Female, Gene Expression Regulation, Neoplastic genetics, HEK293 Cells, Humans, Integrin beta4 genetics, Lymphatic Metastasis, Lymphatic Vessels metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction genetics, Transforming Growth Factor beta1 genetics, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Kalinin, Integrin beta4 metabolism, Lymphatic Vessels cytology, Lymphatic Vessels pathology, Macrophages metabolism, Transforming Growth Factor beta1 metabolism, Triple Negative Breast Neoplasms metabolism
- 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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