Ephrin A1 Stimulates CCL2 Secretion to Facilitate Premetastatic Niche Formation and Promote Gastric Cancer Liver Metastasis

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.