Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Steven E. Reid, Emily J. Kay, Lisa J. Neilson, Anne Theres Henze, Jens Serneels, Ewan J. McGhee, Sandeep Dhayade, Colin Nixon, John B.G. 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. BryantManuel Salmeron-Sanchez, Laura M. Machesky, Leo M. Carlin, Karen Blyth, Massimiliano Mazzone, Sara Zanivan

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42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2373-2389
Number of pages17
JournalEMBO Journal
Volume36
Issue number16
DOIs
Publication statusPublished - Aug 15 2017

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Reid, S. E., Kay, E. J., Neilson, L. J., Henze, A. T., Serneels, J., McGhee, E. J., ... Zanivan, S. (2017). Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO Journal, 36(16), 2373-2389. https://doi.org/10.15252/embj.201694912