Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis but the underlying molecular mechanisms remain elusive. Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM)-signaling and thereby regulates diverse functions including platelet adhesion, aggregation and procoagulant activity. GPVI has been proposed as a safe antithrombotic target as its inhibition is protective in models of arterial thrombosis with only minor effects on hemostasis. Here, we demonstrate that genetic deficiency of platelet GPVI in mice decreases experimental and spontaneous metastasis of colon and breast cancer cells. Similar results were obtained with mice lacking the spleen-tyrosine kinase Syk in platelets, an essential component of the ITAM-signaling cascade. In vitro and in vivo analyses show that mouse, as well as human GPVI, supports platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knock-out approach, we identified Galectin-3 as the major counter-receptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed Galectin-3 utilizes ITAM-signaling components in platelets and favors the extravasation of tumor cells. Finally, we showed that JAQ1 F(ab)2-mediated inhibition of GPVI efficiently impairs platelet-tumor cell interaction and tumor metastasis. Our study reveals a new mechanism by which platelets promote the metastasis of colon and breast cancer cells and suggests that GPVI represents a promising target for antimetastatic therapies.

中文翻译：

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血小板糖蛋白 VI 通过与癌细胞来源的 Galectin-3 相互作用促进转移

越来越多的证据表明血小板在结肠癌和乳腺癌转移中起主要作用，但潜在的分子机制仍然难以捉摸。糖蛋白 VI (GPVI) 是胶原蛋白和纤维蛋白的血小板特异性受体，通过基于免疫受体酪氨酸的激活基序 (ITAM) 信号触发血小板激活，从而调节多种功能，包括血小板粘附、聚集和促凝活性。GPVI 已被提议作为一种安全的抗血栓形成靶点，因为它的抑制作用在动脉血栓形成模型中具有保护作用，而对止血的影响很小。在这里，我们证明小鼠血小板 GPVI 的遗传缺陷会降低结肠癌和乳腺癌细胞的实验性和自发性转移。血小板中缺乏脾酪氨酸激酶 Syk 的小鼠也获得了类似的结果，ITAM 信号级联的重要组成部分。体外和体内分析表明，小鼠以及人类 GPVI 支持血小板粘附到结肠癌细胞和乳腺癌细胞。使用基于 CRISPR/Cas9 的基因敲除方法，我们将 Galectin-3 鉴定为肿瘤细胞上 GPVI 的主要反受体。体内研究表明，血小板 GPVI 和肿瘤细胞表达的 Galectin-3 之间的相互作用利用了血小板中的 ITAM 信号成分并有利于肿瘤细胞的外渗。最后，我们发现 JAQ1 F(ab)2 介导的 GPVI 抑制有效地损害了血小板-肿瘤细胞相互作用和肿瘤转移。我们的研究揭示了血小板促进结肠癌细胞和乳腺癌细胞转移的新机制，并表明 GPVI 是抗转移治疗的一个有希望的靶点。