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Cell Rep. 2019 May 14;27(7):1967-1978.e4. doi: 10.1016/j.celrep.2019.04.076.

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

Author information

1
Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, London, UK. Electronic address: rachel.evans@ucl.ac.uk.
2
Breast Cancer Now Research Unit, King's College London, Guy's Hospital, London, UK.
3
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
4
Pathology Core Facility, University College London Cancer Institute, London, UK.
5
Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, London, UK; Institute for Mathematical and Molecular Biomedicine, King's College London, London, UK.
6
Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, London, UK.
7
King's Health Partners Cancer Biobank, King's College London, London, UK; Research Oncology, Division of Cancer Studies, Guy's Hospital, King's College London, London, UK.
8
Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, London, UK; UCL Cancer Institute, University College London, London, UK.
9
Division of Imaging Sciences and Biomedical Engineering, King's College London, London, UK.
10
Department of Oncology, Cancer Research UK and Medical Research Council, Oxford Institute for Radiation Oncology, University of Oxford, UK.
11
Tissue Engineering and Biophotonics, King's College London, London, UK.
12
Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, London, UK; Breast Cancer Now Research Unit, King's College London, Guy's Hospital, London, UK; UCL Cancer Institute, University College London, London, UK. Electronic address: tony.ng@kcl.ac.uk.

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.

KEYWORDS:

RhoA; TGF-β1; adhesion; cancer; contraction; lymphovasculature; macrophages; remodeling; β4 integrin

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