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Abstract

Systemic spread of tumors is efficiently limited by the host system through the clearance of blood circulating cancer cells. However, cancer cells that evade host recognition are prone to form metastasis. In the present work, the contribution of plasmatic von Willebrand factor (vWF) to recognize blood floating melanoma cells was investigated. I found that blood circulating melanoma cells exposing heparan sulfate (HS) at their surface were strongly encapsulated by plasmatic vWF. Reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF recognition. Assisted by super resolution microscopy, I concluded that vWF formed a tight molecular complex with HS at the cancer cell surface. In microfluidic experiments, mimicking a tumor-activated vascular system, it was demonstrated that vWF-HS complexes prevented vascular adhesion. Single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall. Experiments in vWF knockout mice further confirmed that the HS-vWF complex attenuates hematogenous metastasis, whereas melanoma cells lacking HS evade the antimetastatic recognition by vWF. In line with this, analysis of tissue samples obtained from melanoma patients indicated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlates with metastases and reduced patients’ survival. In conclusion, I have shown that HS-mediated recognition of cancer cells by vWF can reduce their hematogenous spread. My data envisioned that therapeutic promotion of the vWF-HS interaction at the surface of cancer cells may attenuate metastasis.