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)

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 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 > School 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
64798	1	CR-UK Centre renewal	Karen Vousden	Cancer Research UK (CRUK)	18076	RI CANCER SCIENCES