Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer.
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ICR Authors
Authors
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
Ng, T
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
Ng, T
Document Type
Journal Article
Date
2019-05-14
Date Accepted
2019-04-17
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.
Citation
Cell reports, 2019, 27 (7), pp. 1967 - 1978.e4
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247