Abstract
SummaryLymphatic 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.
Highlights
The relationship between tumor and immune cells is often bidirectional and involves both tumor-promoting and -antagonizing mechanisms (Pollard, 2004; Quail and Joyce, 2013)
The Tie2-expressing macrophage (TEM) subset is associated with angiogenesis and lymphatic development (De Palma et al, 2005, 2007; Gordon et al, 2010)
The extent of lymphatic disorganization in the 4T1.2 primary tumors was greater after reconstitution with endogenous tumor-educated bone marrow macrophages (BMMs), compared with noneducated BMMs (0.333 ± 0.3 to 2 ± 0.29; Figure 2D, ii and iii). These results demonstrate that the presence of tumor-associated macrophages (TAMs) results in a disorganized lymphatic vasculature around the primary tumor, that the extent of disorganization is related to overall macrophage levels, and that this occurs at an early time point in tumor development
Summary
The relationship between tumor and immune cells is often bidirectional and involves both tumor-promoting and -antagonizing mechanisms (Pollard, 2004; Quail and Joyce, 2013). Macrophages have been implicated in the promotion of tumor progression and, in particular, breast cancer metastasis (Condeelis and Pollard, 2006; Kitamura et al, 2015; Pollard, 2004; Harney et al, 2015). It remains unclear how certain subsets of tumor-associated macrophages (TAMs) influence breast cancer metastasis spatially, temporally, and at a molecular leve
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