Circadian system disorder induced by aberrantly activated EFNB2-EPHB2 axis leads to facilitated liver metastasis in gastric cancer

Abstract

Background: Liver is one of the most preferred destinations for distant metastasis of gastric cancer (GC) and liver metastasis usually predicts poor prognosis. The achievement of liver metastasis requires continued cross-talk of complex members in tumor microenvironment (TME) including tumor associated macrophages (TAMs).

Methods: Results from 35 cases of ex vivo cultured living tissues of GC liver metastasis have elucidated that circadian rhythm disorder (CRD) of key molecules involved in circadian timing system (CTS) facilitates niche outgrowth. We next analyzed 69 cases of liver metastasis from patients bearing GC and designed co-culture or 3D cell culture, discovering that TAMs expressing EFNB2 could interact with tumor cell expressing EPHB2 for forward downstream signaling and lead to CRD of tumor cells. Moreover, we performed intrasplenic injection models assessed by CT combined 3D organ reconstruction bioluminescence imaging to study liver metastasis and utilized the clodronate treatment, bone marrow transplantation or EPH inhibitor for in vivo study followed by exploring the clinical therapeutic value of which in patient derived xenograft (PDX) mouse model.

Results: Ex vivo studies demonstrated that CRD of key CTS molecules facilitates niche outgrowth in liver metastases. In vitro studies revealed that TAMs expressing EFNB2 interact with tumor cells expressing EPHB2, leading to CRD and downstream signaling activation. The underlying mechanism is the enhancement of the Warburg effect in metastatic niches.

Conclusion: Overall, we aim to uncover the mechanism in TAMs induced CRD which promotes liver metastasis of GC and provide novel ideas for therapeutic strategies.

Keywords: EFNB2-EPHB2 axis; Gastric cancer; Liver metastasis; Tumor microenvironment; Warburg effect.