Integrin-mediated macrophage adhesion promotes lymphovascular dissemination in breast cancer

TY - JOUR

T1 - Integrin-mediated macrophage adhesion promotes lymphovascular dissemination in breast cancer

AU - Evans, Rachel

AU - Flores-Borja, Fabian

AU - Nassiri, Sina

AU - Miranda, Elena

AU - Lawler, Katherine

AU - Grigoriadis, Anita

AU - Monypenny, James

AU - Gillett, Cheryl

AU - Owen, Julie

AU - Gordon, Peter

AU - Male, Victoria

AU - Cheung, Anthony

AU - Noor, Farzana

AU - Barber, Paul

AU - Marlow, Rebecca

AU - Francesch-Domenech, Erika

AU - Fruhwirth, Gilbert

AU - Squadrito, Mario

AU - Vojnovic, Borivoj

AU - Tutt, Andrew

AU - Festy, Frederic

AU - De Palma, Michele

AU - Ng, Tony

PY - 2019/5/14

Y1 - 2019/5/14

N2 - 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.

AB - 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.

KW - RhoA

KW - TGF-β1

KW - adhesion

KW - cancer

KW - contraction

KW - lymphovasculature

KW - macrophages

KW - remodeling

KW - β4 integrin

UR - https://www.scopus.com/pages/publications/85065064106

U2 - 10.1016/j.celrep.2019.04.076

DO - 10.1016/j.celrep.2019.04.076

M3 - Article

SN - 2211-1247

VL - 27

SP - 1967-1978.e4

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -