Cui Yun, Chang Yongxia, Ma Xixi, Sun Meng, Huang Yuliang, Yang Feng, Li Shuang, Zhuo Wei, Liu Wei, Yang Bo, Lin Aifu, Ou Guangshuo, Yang Yuehong, Xie Shanshan, Zhou Tianhua
Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
Cancer Res. 2025 Jan 15;85(2):263-276. doi: 10.1158/0008-5472.CAN-24-1254.
The liver is a primary target for distal metastasis of gastric cancer. The hepatic premetastatic 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 gastric cancer 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 gastric cancer cells significantly increased C-C motif chemokine ligand 2 (CCL2) secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStC) 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 gastric cancer cells. Moreover, high CCL2 expression correlated with poor survival in patients with cancer. Overall, these findings reveal that EFNA1 signaling in gastric cancer cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic PMN that supports liver metastasis. Significance: Cross-talk between gastric cancer cells and hepatic stellate cells mediated by the EFNA1/CCL2 axis induces premetastatic niche development to facilitate metastatic spread, nominating CCL2 as a therapeutic target to suppress liver metastasis.
肝脏是胃癌远处转移的主要靶器官。肝脏前转移微环境（PMN）促进原发肿瘤与肝脏之间的关键通讯，从而在肝转移中发挥重要作用。确定驱动胃癌中PMN形成的分子机制有助于制定预防和治疗肝转移的策略。在此，我们揭示了 Ephrin A1（EFNA1）信号在PMN形成过程中的作用。胃癌细胞中EFNA1的过表达通过Hippo-YAP途径显著增加C-C基序趋化因子配体2（CCL2）的分泌。分泌的CCL2通过WNT/β-连环蛋白途径激活肝脏PMN内的肝星状细胞（HStC）。抑制CCL2可显著抑制HStC激活，并减少胃癌细胞中EFNA1信号触发的肝转移。此外，CCL2高表达与癌症患者的不良生存相关。总体而言，这些发现表明，胃癌细胞中的EFNA1信号上调CCL2，CCL2激活HStC以促使支持肝转移的肝脏PMN形成。意义：由EFNA1/CCL2轴介导的胃癌细胞与肝星状细胞之间的串扰诱导前转移微环境的发展以促进转移扩散，将CCL2确定为抑制肝转移的治疗靶点。
