Developing tumors interact with the surrounding microenvironment. Myeloid cells exert both anti- and pro-tumor functions and chemokines are known to drive immune cell migration towards cancer cells. It is documented that CXCR4 signaling supports tumor metastasis formation in tissues where CXCL12, its cognate ligand, is abundant. On the other hand, the role of the neutrophilic CXCR4 signaling in driving cancer invasion and metastasis formation is poorly understood. Here, we use the zebrafish xenotransplantation model to study the role of CXCR4 signaling in driving the interaction between invasive human tumor cells and host neutrophils, supporting early metastasis formation. We found that zebrafish cxcr4 (cxcr4b) is highly expressed in neutrophils and experimental micrometastases fail to form in mutant larvae lacking a functional Cxcr4b. We demonstrated that Cxcr4b controls neutrophil number and motility and showed that Cxcr4b transcriptomic signature relates to motility and adhesion regulation in neutrophils in tumor-naïve larvae. Finally, Cxcr4b deficient neutrophils failed to interact with cancer cells initiating early metastatic events. In conclusion, we propose that CXCR4 signaling supports the interaction between tumor cells and host neutrophils in developing tumor metastases. Therefore, targeting CXCR4 on tumor cells and neutrophils could serve as a double bladed razor to limit cancer progression.

发育中的肿瘤与周围的微环境相互作用。髓样细胞同时发挥抗肿瘤和促肿瘤作用，并且已知趋化因子可驱动免疫细胞向癌细胞迁移。据证明，CXCR4信号支持在其同源配体CXCL12丰富的组织中的肿瘤转移形成。另一方面，人们对中性粒细胞CXCR4信号在驱动癌症侵袭和转移形成中的作用了解甚少。在这里，我们使用斑马鱼异种移植模型来研究CXCR4信号在驱动浸润性人类肿瘤细胞与宿主嗜中性粒细胞之间相互作用，支持早期转移形成中的作用。我们发现斑马鱼cxcr4（cxcr4b）在中性粒细胞中高表达，实验性微转移未能在缺乏功能性Cxcr4b的突变幼虫中形成。我们证明了Cxcr4b控制中性粒细胞的数量和运动性，并表明Cxcr4b转录组学特征与幼稚中性粒细胞中性粒细胞的运动性和粘附调节有关。最后，缺乏Cxcr4b的中性粒细胞未能与癌细胞相互作用，从而引发早期转移事件。总之，我们建议CXCR4信号传导支持肿瘤细胞与宿主嗜中性粒细胞之间相互作用，从而促进肿瘤转移。因此，将CXCR4靶向肿瘤细胞和嗜中性粒细胞可以用作剃刀，以限制癌症的进展。