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Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium
Author(s) -
Reid Steven E,
Kay Emily J,
Neilson Lisa J,
Henze AnneTheres,
Serneels Jens,
McGhee Ewan J,
Dhayade Sandeep,
Nixon Colin,
Mackey John BG,
Santi Alice,
Swaminathan Karthic,
Athineos Dimitris,
Papalazarou Vasileios,
Patella Francesca,
RománFernández Álvaro,
ElMaghloob Yasmin,
HernandezFernaud Juan Ramon,
Adams Ralf H,
Ismail Shehab,
Bryant David M,
SalmeronSanchez Manuel,
Machesky Laura M,
Carlin Leo M,
Blyth Karen,
Mazzone Massimiliano,
Zanivan Sara
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694912
Subject(s) - cancer , library science , medicine , computer science
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 CCN 1/ CYR 61 is highly regulated by stiffness in endothelial cells. We show that stiffness‐induced CCN 1 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 CCN 1, is therefore a potential yet unappreciated mechanism to impair metastasis.