期刊
CANCER DISCOVERY
卷 10, 期 11, 页码 1758-1773出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0036
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资金
- V. Bronte grants of the Italian Association for Cancer Research [18603, 12182]
- Cancer Research Institute (Clinic and Laboratory Integration Program)
- Cariverona Foundation
- Qatar National Priority Research Program [NPRP11S-1211-170086]
- AIRC/FIRC fellowship
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG20583]
- Institutional funds of Universita Cattolica del Sacro Cuore (UCSC) [D1-2018/2019]
- Euronanomed III [723770]
- IOV 5 x 1000 Intramural Research Grant Project [BIGID219MARI]
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.
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