Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Steven E. Reid; Emily J. Kay; Lisa J. Neilson; Anne Theres Henze; Jens Serneels; Ewan J. McGhee; Sandeep Dhayade; Colin Nixon; John B.G. Mackey; Alice Santi; Karthic Swaminathan; Dimitris Athineos; Vasileios Papalazarou; Francesca Patella; Álvaro Román-Fernández; Yasmin ElMaghloob; Juan Ramon Hernandez-Fernaud; Ralf H. Adams; Shehab Ismail; David M. Bryant; Manuel Salmeron-Sanchez; Laura M. Machesky; Leo M. Carlin; Karen Blyth; Massimiliano Mazzone; Sara Zanivan

doi:10.15252/embj.201694912

Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Steven E. Reid, Emily J. Kay, Lisa J. Neilson, Anne Theres Henze, Jens Serneels, Ewan J. McGhee, Sandeep Dhayade, Colin Nixon, John B.G. Mackey, Alice Santi, Karthic Swaminathan, Dimitris Athineos, Vasileios Papalazarou, Francesca Patella, Álvaro Román-Fernández, Yasmin ElMaghloob, Juan Ramon Hernandez-Fernaud, Ralf H. Adams, Shehab Ismail, David M. BryantManuel Salmeron-Sanchez, Laura M. Machesky, Leo M. Carlin, Karen Blyth, Massimiliano Mazzone, Sara Zanivan

Research output: Contribution to journal › Article › peer-review

107 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2373-2389
Number of pages	17
Journal	EMBO Journal
Volume	36
Issue number	16
DOIs	https://doi.org/10.15252/embj.201694912
Publication status	Published - Aug 15 2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

Neuroscience(all)
Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Reid, S. E., Kay, E. J., Neilson, L. J., Henze, A. T., Serneels, J., McGhee, E. J., Dhayade, S., Nixon, C., Mackey, J. B. G., Santi, A., Swaminathan, K., Athineos, D., Papalazarou, V., Patella, F., Román-Fernández, Á., ElMaghloob, Y., Hernandez-Fernaud, J. R., Adams, R. H., Ismail, S., ... Zanivan, S. (2017). Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO Journal, 36(16), 2373-2389. https://doi.org/10.15252/embj.201694912

Reid, SE, Kay, EJ, Neilson, LJ, Henze, AT, Serneels, J, McGhee, EJ, Dhayade, S, Nixon, C, Mackey, JBG, Santi, A, Swaminathan, K, Athineos, D, Papalazarou, V, Patella, F, Román-Fernández, Á, ElMaghloob, Y, Hernandez-Fernaud, JR, Adams, RH, Ismail, S, Bryant, DM, Salmeron-Sanchez, M, Machesky, LM, Carlin, LM, Blyth, K, Mazzone, M & Zanivan, S 2017, 'Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium', EMBO Journal, vol. 36, no. 16, pp. 2373-2389. https://doi.org/10.15252/embj.201694912

@article{5717885ab2a1426db92e08bf8de929ab,

title = "Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium",

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.",

author = "Reid, {Steven E.} and Kay, {Emily J.} and Neilson, {Lisa J.} and Henze, {Anne Theres} and Jens Serneels and McGhee, {Ewan J.} and Sandeep Dhayade and Colin Nixon and Mackey, {John B.G.} and Alice Santi and Karthic Swaminathan and Dimitris Athineos and Vasileios Papalazarou and Francesca Patella and {\'A}lvaro Rom{\'a}n-Fern{\'a}ndez and Yasmin ElMaghloob and Hernandez-Fernaud, {Juan Ramon} and Adams, {Ralf H.} and Shehab Ismail and Bryant, {David M.} and Manuel Salmeron-Sanchez and Machesky, {Laura M.} and Carlin, {Leo M.} and Karen Blyth and Massimiliano Mazzone and Sara Zanivan",

note = "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: {\textcopyright} 2017 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license",

year = "2017",

month = aug,

day = "15",

doi = "10.15252/embj.201694912",

language = "English",

volume = "36",

pages = "2373--2389",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Nature Publishing Group",

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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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DO - 10.15252/embj.201694912

M3 - Article

C2 - 28694244

AN - SCOPUS:85022336112

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VL - 36

SP - 2373

EP - 2389

JO - EMBO Journal

JF - EMBO Journal

IS - 16

ER -

Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Abstract

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