The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.

中文翻译：

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肝配蛋白 A1 刺激 CCL2 分泌促进转移前生态位形成并促进胃癌肝转移


肝脏是胃癌 （GC） 远端转移的主要靶标。肝脏转移前生态位 （PMN） 促进原发肿瘤和肝脏之间的重要通讯，从而在肝转移中起重要作用。确定 GC 中驱动 PMN 形成的分子机制有助于制定预防和治疗肝转移的策略。在这里，我们发现了肝配蛋白 A1 （EFNA1） 信号转导在 PMN 发育中的作用。EFNA1 在 GC 细胞中的过表达通过 Hippo-YAP 通路显著增加 CCL2 的分泌。分泌的 CCL2 通过 WNT/β-catenin 通路在肝脏 PMN 内激活肝星状细胞 （HStC）。抑制 CCL2 显著抑制 GC 细胞中 EFNA1 信号触发的 HStC 活化并减少肝转移。此外，高 CCL2 表达与 GC 患者的不良生存率相关。总体而言，这些发现揭示了 GC 细胞中的 EFNA1 信号转导上调 CCL2，从而激活 HStC 以建立支持肝转移的肝脏转移前生态位。