TY - JOUR
T1 - Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium
AU - Reid, Steven E.
AU - Kay, Emily J.
AU - Neilson, Lisa J.
AU - Henze, Anne Theres
AU - Serneels, Jens
AU - McGhee, Ewan J.
AU - Dhayade, Sandeep
AU - Nixon, Colin
AU - Mackey, John B.G.
AU - Santi, Alice
AU - Swaminathan, Karthic
AU - Athineos, Dimitris
AU - Papalazarou, Vasileios
AU - Patella, Francesca
AU - Román-Fernández, Álvaro
AU - ElMaghloob, Yasmin
AU - Hernandez-Fernaud, Juan Ramon
AU - Adams, Ralf H.
AU - Ismail, Shehab
AU - Bryant, David M.
AU - Salmeron-Sanchez, Manuel
AU - Machesky, Laura M.
AU - Carlin, Leo M.
AU - Blyth, Karen
AU - Mazzone, Massimiliano
AU - Zanivan, Sara
N1 - Funding Information:
We would like to thank David Strachan for developing the ImageJ macro for analysis of tumor vascularity and pericyte coverage and Margaret O'Prey from the Beatson Advanced Imaging Resource, the BSU and histology facilities at the CRUK Beatson Institute, Evarest Onwubiko and Christopher Baxter for help with in vivo work, Clare Orange for histopathology services, NHS Greater Glasgow and Clyde Biorepository for the umbilical cords, and Prof Hans Jorg Fehling and the European Mouse Mutant Archive (EMMA) for providing the Rosa26flSTOP-tdRFP mice. We thank Jim Norman for fruitful discussions, and Jon Lakins and Valerie Weaver for the improvements in the methodology of generating PAGs for cell culture. This work was funded by Cancer Research UK (CRUK Beatson Institute C596/A17196, CRUK Glasgow Centre C596/A18076 and S.Z. C596/A12935). We thank the PRIDE team.
Publisher Copyright:
© 2017 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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.
AB - 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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U2 - 10.15252/embj.201694912
DO - 10.15252/embj.201694912
M3 - Article
C2 - 28694244
AN - SCOPUS:85022336112
SN - 0261-4189
VL - 36
SP - 2373
EP - 2389
JO - EMBO Journal
JF - EMBO Journal
IS - 16
ER -
