Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium |
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| Authors: | Steven E Reid Emily J Kay Lisa J Neilson Anne‐Theres Henze Jens Serneels Ewan J McGhee Sandeep Dhayade Colin Nixon John BG Mackey Alice Santi Karthic Swaminathan Dimitris Athineos Vasileios Papalazarou Francesca Patella Álvaro Román‐Fernández Yasmin ElMaghloob Juan Ramon Hernandez‐Fernaud Ralf H Adams Shehab Ismail David M Bryant Manuel Salmeron‐Sanchez Laura M Machesky Leo M Carlin Karen Blyth Massimiliano Mazzone Sara Zanivan |
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| Affiliation: | 1. Cancer Research UK Beatson Institute, Glasgow, UK;2. Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium;3. Inflammation, Repair and Development, Imperial College London, London, UK;4. Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, UK;5. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK;6. Department of Tissue Morphogenesis, Faculty of Medicine, Max‐Planck‐Institute for Molecular Biomedicine, University of Münster, Münster, Germany;7. Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium |
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| Abstract: | Tumor progression alters the composition and physical properties of the extracellular matrix. Particularly, increased matrix stiffness has profound effects on tumor growth and metastasis. While endothelial cells are key players in cancer progression, the influence of tumor stiffness on the endothelium and the impact on metastasis is unknown. Through quantitative mass spectrometry, we find that the matricellular protein CCN1/CYR61 is highly regulated by stiffness in endothelial cells. We show that stiffness‐induced CCN1 activates β‐catenin nuclear translocation and signaling and that this contributes to upregulate N‐cadherin levels on the surface of the endothelium, in vitro. This facilitates N‐cadherin‐dependent cancer cell–endothelium interaction. Using intravital imaging, we show that knockout of Ccn1 in endothelial cells inhibits melanoma cancer cell binding to the blood vessels, a critical step in cancer cell transit through the vasculature to metastasize. Targeting stiffness‐induced changes in the vasculature, such as CCN1, is therefore a potential yet unappreciated mechanism to impair metastasis. |
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| Keywords: | CCN1/CYR61 stiffness blood vessels proteomics cancer metastasis |
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