Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients’ survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression.

硫酸乙酰肝素 (HS) 是一种带高负电荷的糖胺聚糖，普遍存在于所有组织中，也暴露于哺乳动物细胞表面。大量分子，例如生长因子、细胞因子或凝血因子，都带有 HS 结合位点。因此，HS 控制细胞与其环境的通讯，从而控制许多生理和病理生理过程，例如细胞粘附、迁移和癌细胞转移。在目前的工作中，我们发现血液循环黑色素瘤细胞暴露的 HS 将大量血浆血管性血友病因子 (vWF) 募集到细胞表面。超分辨率显微镜辅助分析表明 HS 和 vWF 形成了紧密的分子复合物。HS 的酶促去除或 HS 生物合成的基因工程表明 HS 链长度的减少或 HS 的完全缺乏与显着减少的 vWF 封装有关。在模拟肿瘤激活的血管系统的微流体实验中，我们发现 vWF-HS 复合物可防止血管粘连。与此一致，单分子力谱表明 vWF-HS 复合物促进循环癌细胞从血管壁排斥以抵消转移。在野生型和 vWF 敲除小鼠中的实验证实，黑色素瘤细胞表面的 HS-vWF 复合物减弱了血行转移，而缺乏 HS 的黑色素瘤细胞逃避了 vWF 的抗转移识别。对从黑色素瘤患者获得的组织样本的分析证实，转移性黑色素瘤细胞产生的 HS 较少。转录组数据进一步表明 HS 相关基因的减弱表达与转移相关并降低了患者的存活率。总之，我们表明 HS 介导的血浆 vWF 与细胞表面的结合可以减少黑色素瘤的血行扩散。HS 水平低的癌细胞逃避 vWF 识别，因此容易形成转移。因此，暴露于 HS 的癌细胞的治疗性扩增可以防止肿瘤进展。我们发现 HS 介导的血浆 vWF 与细胞表面的结合可以减少黑色素瘤的血行扩散。HS 水平低的癌细胞逃避 vWF 识别，因此容易形成转移。因此，暴露于 HS 的癌细胞的治疗性扩增可以防止肿瘤进展。我们发现 HS 介导的血浆 vWF 与细胞表面的结合可以减少黑色素瘤的血行扩散。HS 水平低的癌细胞逃避 vWF 识别，因此容易形成转移。因此，暴露于 HS 的癌细胞的治疗性扩增可以防止肿瘤进展。