Abstract
Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs. SIGNIFICANCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP-TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.This article is highlighted in the In This Issue feature, p. 1611.
Highlights
SIGnIFICAnCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth
A total of 5,170 myeloid cells were grouped into 14 different clusters that we define as six macrophage clusters (MΦ_1-6); two monocyte clusters, Mono_1 (Ly6c2+Ccr2+ inflammatory monocytes, iMo) and Mono_2; four dendritic cell (DC) clusters (Cd209a+ DC_1, Ccr7− DC_2, Cd24a+ DC_3 and Ccr7+ DC_4); a mixed cluster of macrophages and DCs (MΦ-DC); and a cluster of PMN-like cells, which did not express the canonical neutrophil marker (i.e., Ly6g; Fig. 1A; Supplementary Fig. S1A and S1B; Supplementary Data S1)
Macrophages represent a heterogeneous cell population that consists in a continuum of different states that cannot be completely recapitulated in the bipolar M1–M2 classification
Summary
SIGnIFICAnCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. In solid cancers, tumorassociated macrophages (TAM) are abundant immune cells, and their presence correlates with a poor prognosis [2,3,4,5]. Different molecules influence the macrophage-assisted metastatic process, such as colony-stimulating factor 1 Combining endocytosis with directional exocytosis, DAB2 concentrates shuttling proteins into specific sites of the cell membrane, favoring interplay with the surrounding extracellular matrix Changes in ECM composition, tissue stiffness, and integrin repertoire govern cell directional migration in response to gradients of adhesive molecules and matrix rigidity, migratory processes known as haptotaxis and durotaxis, respectively [18]. The mechanisms that control ECM remodeling and cellular movement during metastatic invasion are ill-defined, primarily because information about specific molecular interactions among cells and matrix in the context of macrophage-assisted metastasis is missing. We demonstrate the value of the gene encoding DAB2 as a potential prognostic marker for disease progression in patients, either as a single gene or in association with other tumor-promoting genes
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