Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

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. Synopsis Mass spectrometric identification of CCN1 provides insight into how tumor matrix stiffness affects tumor growth and metastasis by increasing endothelial cell‐cancer cell adhesion, a key step in cancer cell intravasation into the vasculature. Increased tumor matrix stiffness upregulates CCN1/CYR61 expression in endothelial cells. CCN1 induces N‐cadherin expression via β‐catenin activity. Increased N‐cadherin surface expression mediates cancer cell‐endothelium adhesion. CCN1 deficiency in endothelial cells decreases cancer‐endothelial cell interactions in vivo . Graphical Abstract Quantitative mass spectrometry identifies CCN1 as the basis for matrix stiffness effects on tumor progression via mediating adhesion to endothelial cells and thereby cancer cell intravasation into the vasculature.