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Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Reid, Steven E. LU ; Kay, Emily J. ; Neilson, Lisa J. ; Henze, Anne Theres ; Serneels, Jens ; McGhee, Ewan J. ; Dhayade, Sandeep ; Nixon, Colin ; Mackey, John B.G. and Santi, Alice , et al. (2017) In EMBO Journal 36(16). p.2373-2389
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
subject
keywords
blood vessels, cancer metastasis, CCN1/CYR61, proteomics, stiffness
in
EMBO Journal
volume
36
issue
16
pages
2373 - 2389
publisher
Oxford University Press
external identifiers
  • scopus:85022336112
  • pmid:28694244
ISSN
0261-4189
DOI
10.15252/embj.201694912
language
English
LU publication?
no
id
d1c134e8-19af-459a-8065-61f25d7edd46
date added to LUP
2020-09-22 14:51:48
date last changed
2024-06-14 00:38:52
@article{d1c134e8-19af-459a-8065-61f25d7edd46,
  abstract     = {{<p>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.</p>}},
  author       = {{Reid, Steven E. and Kay, Emily J. and Neilson, Lisa J. and Henze, Anne Theres and Serneels, Jens and McGhee, Ewan J. and Dhayade, Sandeep and Nixon, Colin and Mackey, John B.G. and Santi, Alice and Swaminathan, Karthic and Athineos, Dimitris and Papalazarou, Vasileios and Patella, Francesca and Román-Fernández, Álvaro and ElMaghloob, Yasmin and Hernandez-Fernaud, Juan Ramon and Adams, Ralf H. and Ismail, Shehab and Bryant, David M. and Salmeron-Sanchez, Manuel and Machesky, Laura M. and Carlin, Leo M. and Blyth, Karen and Mazzone, Massimiliano and Zanivan, Sara}},
  issn         = {{0261-4189}},
  keywords     = {{blood vessels; cancer metastasis; CCN1/CYR61; proteomics; stiffness}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{16}},
  pages        = {{2373--2389}},
  publisher    = {{Oxford University Press}},
  series       = {{EMBO Journal}},
  title        = {{Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium}},
  url          = {{http://dx.doi.org/10.15252/embj.201694912}},
  doi          = {{10.15252/embj.201694912}},
  volume       = {{36}},
  year         = {{2017}},
}