Tumor Matrix Stiffness Promotes Metastatic Cancer Cell Interaction with the Endothelium

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Jul 12

PMID 28694244

Citations 89

Authors

Steven E Reid

Emily J Kay

Lisa J Neilson

Anne-Theres Henze

Jens Serneels

Ewan J McGhee

Sandeep Dhayade

Colin Nixon

John Bg Mackey

Alice Santi

Karthic Swaminathan

Dimitris Athineos

Vasileios Papalazarou

Francesca Patella

Alvaro Roman-Fernandez

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

Affiliations

Soon will be listed here.

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, This facilitates N-cadherin-dependent cancer cell-endothelium interaction. Using intravital imaging, we show that knockout of 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.

Citing Articles

Local soft niches in mechanically heterogeneous primary tumors promote brain metastasis via mechanotransduction-mediated HDAC3 activity.

Tang K, Zheng Y, Hu G, Xin Y, Li K, Zhang C Sci Adv. 2025; 11(9):eadq2881.

PMID: 40009679 PMC: 11864190. DOI: 10.1126/sciadv.adq2881.

Mechanical signatures in cancer metastasis.

Agrawal A, Javanmardi Y, Watson S, Serwinski B, Djordjevic B, Li W NPJ Biol Phys Mech. 2025; 2(1):3.

PMID: 39917412 PMC: 11794153. DOI: 10.1038/s44341-024-00007-x.

A multifunctional sensor for cell traction force, matrix remodeling and biomechanical assays in self-assembled 3D tissues in vitro.

Emon B, Joy M, Drennan W, Saif M Nat Protoc. 2025; .

PMID: 39856342 DOI: 10.1038/s41596-024-01106-8.

Insights into the mechanisms, regulation, and therapeutic implications of extracellular matrix stiffness in cancer.

Zhang X, Al-Danakh A, Zhu X, Feng D, Yang L, Wu H Bioeng Transl Med. 2025; 10(1):e10698.

PMID: 39801760 PMC: 11711218. DOI: 10.1002/btm2.10698.

Viscoelasticity in 3D Cell Culture and Regenerative Medicine: Measurement Techniques and Biological Relevance.

Eliahoo P, Setayesh H, Hoffman T, Wu Y, Li S, Treweek J ACS Mater Au. 2024; 4(4):354-384.

PMID: 39006396 PMC: 11240420. DOI: 10.1021/acsmaterialsau.3c00038.

References

Kalluri R, Zeisberg M . Fibroblasts in cancer. Nat Rev Cancer. 2006; 6(5):392-401. DOI: 10.1038/nrc1877. View

Saunders R, Hammer D . Assembly of Human Umbilical Vein Endothelial Cells on Compliant Hydrogels. Cell Mol Bioeng. 2011; 3(1):60-67. PMC: 3132815. DOI: 10.1007/s12195-010-0112-4. View

Patella F, Neilson L, Athineos D, Erami Z, Anderson K, Blyth K . In-Depth Proteomics Identifies a Role for Autophagy in Controlling Reactive Oxygen Species Mediated Endothelial Permeability. J Proteome Res. 2016; 15(7):2187-97. DOI: 10.1021/acs.jproteome.6b00166. View

Peitz M, Pfannkuche K, Rajewsky K, Edenhofer F . Ability of the hydrophobic FGF and basic TAT peptides to promote cellular uptake of recombinant Cre recombinase: a tool for efficient genetic engineering of mammalian genomes. Proc Natl Acad Sci U S A. 2002; 99(7):4489-94. PMC: 123675. DOI: 10.1073/pnas.032068699. View

Miller B, Morton J, Pinese M, Saturno G, Jamieson N, McGhee E . Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 2015; 7(8):1063-76. PMC: 4551344. DOI: 10.15252/emmm.201404827. View

Jarvelainen H, Sainio A, Koulu M, Wight T, Penttinen R . Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol Rev. 2009; 61(2):198-223. PMC: 2830117. DOI: 10.1124/pr.109.001289. View

Levental K, Yu H, Kass L, Lakins J, Egeblad M, Erler J . Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009; 139(5):891-906. PMC: 2788004. DOI: 10.1016/j.cell.2009.10.027. View

Huang Y, Lan Q, Lorusso G, Duffey N, Ruegg C . The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget. 2016; 8(6):9200-9215. PMC: 5354725. DOI: 10.18632/oncotarget.13677. View

Xie D, Yin D, Tong X, OKelly J, Mori A, Miller C . Cyr61 is overexpressed in gliomas and involved in integrin-linked kinase-mediated Akt and beta-catenin-TCF/Lef signaling pathways. Cancer Res. 2004; 64(6):1987-96. DOI: 10.1158/0008-5472.can-03-0666. View

10.

Wei S, Fattet L, Tsai J, Guo Y, Pai V, Majeski H . Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015; 17(5):678-88. PMC: 4452027. DOI: 10.1038/ncb3157. View

11.

Mui K, Bae Y, Gao L, Liu S, Xu T, Radice G . N-Cadherin Induction by ECM Stiffness and FAK Overrides the Spreading Requirement for Proliferation of Vascular Smooth Muscle Cells. Cell Rep. 2015; 10(9):1477-1486. PMC: 4560684. DOI: 10.1016/j.celrep.2015.02.023. View

12.

Lakins J, Chin A, Weaver V . Exploring the link between human embryonic stem cell organization and fate using tension-calibrated extracellular matrix functionalized polyacrylamide gels. Methods Mol Biol. 2012; 916:317-50. DOI: 10.1007/978-1-61779-980-8_24. View

13.

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B . Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015; 17(9):1218-27. PMC: 6186417. DOI: 10.1038/ncb3216. View

14.

Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C . Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb). 2015; 7(10):1120-34. PMC: 4593730. DOI: 10.1039/c5ib00040h. View

15.

Fidler I . Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 1975; 35(1):218-24. View

16.

Vizcaino J, Cote R, Csordas A, Dianes J, Fabregat A, Foster J . The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2012; 41(Database issue):D1063-9. PMC: 3531176. DOI: 10.1093/nar/gks1262. View

17.

Geiger T, Wisniewski J, Cox J, Zanivan S, Kruger M, Ishihama Y . Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. Nat Protoc. 2011; 6(2):147-57. DOI: 10.1038/nprot.2010.192. View

18.

Wisniewski J, Zougman A, Mann M . Combination of FASP and StageTip-based fractionation allows in-depth analysis of the hippocampal membrane proteome. J Proteome Res. 2009; 8(12):5674-8. DOI: 10.1021/pr900748n. View

19.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

20.

Kojima Y, Acar A, Eaton E, Mellody K, Scheel C, Ben-Porath I . Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010; 107(46):20009-14. PMC: 2993333. DOI: 10.1073/pnas.1013805107. View