Disabled Homolog 2 Controls Prometastatic Activity of Tumor- Associated Macrophages
- 1 November 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (11), 1758-1773
- https://doi.org/10.1158/2159-8290.CD-20-0036
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.Other Versions
Funding Information
- Italian Association for Cancer Research (18603, 12182)
- Qatar National Priority Research Program 2017 (NPRP11S-1211-170086)
- AIRC
- Associazione Italiana per la Ricerca sul Cancro (IG20583)
- Institutional funds of Università Cattolica del Sacro Cuore (D1-2018/2019)
- EuroNanoMed III (723770)
- IOV 5 × 1000 Intramural Research Grant Project (N.BIGID219MARI)
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