Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

• Steven E Reid ^[3] ; Emily J Kay ^[3] ; Lisa J Neilson ^[3] ; Anne‐Theres Henze ^[4] ; Jens Serneels ^[4] ; Ewan J McGhee ^[3] ; Sandeep Dhayade ^[3] ; Colin Nixon ^[3] ; John BG Mackey ^[5] ; Alice Santi ^[3] ; Karthic Swaminathan ^[3] ; Dimitris Athineos ^[3] ; Vasileios Papalazarou ^[1] ; Francesca Patella ^[3] ; Álvaro Román‐Fernández ^[1] ; Yasmin ElMaghloob ^[3] ; Juan Ramon Hernandez‐Fernaud ^[3] ; Ralf H Adams ^[2] ; Shehab Ismail ^[3] ; David M Bryant ^[1] ; Manuel Salmeron‐Sanchez ^[1] ; Laura M Machesky ^[3] ; Leo M Carlin ^[3] ; Karen Blyth ^[3] ; Massimiliano Mazzone ^[6] ; Sara Zanivan ^[1]
  1. [1] University of Glasgow

     University of Glasgow

     Reino Unido

     
  2. [2] University of Münster

     University of Münster

     Kreisfreie Stadt Münster, Alemania

     
  3. [3] 1 Cancer Research UK Beatson Institute Glasgow UK
  4. [4] 2 Lab of Tumor Inflammation and Angiogenesis Center for Cancer Biology VIB Leuven Belgium
  5. [5] 1 Cancer Research UK Beatson Institute Glasgow UK; 3 Inflammation, Repair and Development Imperial College London London UK
  6. [6] 2 Lab of Tumor Inflammation and Angiogenesis Center for Cancer Biology VIB Leuven Belgium; 7 Lab of Tumor Inflammation and Angiogenesis Center for Cancer Biology Department of Oncology KU Leuven Leuven Belgium

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 16, 2017, págs. 2373-2389
• Idioma: inglés
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  • 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.