Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Reid, S. E. et al. (2017) Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO Journal, 36(16), pp. 2373-2389. (doi:10.15252/embj.201694912) (PMID:28694244) (PMCID:PMC5556271)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Roman Fernandez, Mr Alvaro and Blyth, Professor Karen and Mackey, John and Salmeron-Sanchez, Professor Manuel and Nixon, Mr Colin and McGhee, Dr Ewan and Neilson, Ms Lisa and Elmaghloob, Yasmin Adel Elsayed and Carlin, Dr Leo and Machesky, Professor Laura and Zanivan, Professor Sara Rossana and Patella, Dr Francesca and Kay, Emily and Ismail, Dr Shehab and Bryant, Dr David and Athineos, Mr Dimitris and Papalazarou, Vasileios
Authors: Reid, S. E., Kay, E., Neilson, L. J., Henze, A.-T., Serneels, J., McGhee, E. J., Dhayade, S., Nixon, C., Mackey, J., Santi, A., Swaminathan, K., Athineos, D., Papalazarou, V., Patella, F., Román-Fernández, Á., Elmaghloob, Y., Hernandez-Fernaud, J. R., Adams, R. H., Ismail, S., Bryant, D. M., Salmeron-Sanchez, M., Machesky, L. M., Carlin, L. M., Blyth, K., Mazzone, M., and Zanivan, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Published Online:10 July 2017
Copyright Holders:Copyright © 2017 Cancer Research UK Beatson Institute
First Published:First published in EMBO Journal 36(16):2373-2389
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES

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