Li Qing, Lin Yuxuan, Ni Bo, Geng Haigang, Wang Chaojie, Zhao Enhao, Zhu Chunchao
Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China.
Cell Oncol (Dordr). 2024 Dec;47(6):2113-2134. doi: 10.1007/s13402-024-00991-1. Epub 2024 Sep 19.
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).
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.
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.
Overall, we aim to uncover the mechanism in TAMs induced CRD which promotes liver metastasis of GC and provide novel ideas for therapeutic strategies.
肝脏是胃癌（GC）远处转移最常见的靶器官之一，肝转移通常预示着预后不良。肝转移的发生需要肿瘤微环境（TME）中包括肿瘤相关巨噬细胞（TAM）在内的复杂成员持续相互作用。
35例GC肝转移离体培养活组织的结果表明，昼夜节律系统（CTS）中关键分子的昼夜节律紊乱（CRD）促进了生态位的生长。接下来，我们分析了69例GC患者的肝转移情况，并设计了共培养或3D细胞培养，发现表达EFNB2的TAM可以与表达EPHB2的肿瘤细胞相互作用，进行正向下游信号传导，导致肿瘤细胞的CRD。此外，我们通过CT联合3D器官重建生物发光成像评估的脾内注射模型研究肝转移，并使用氯膦酸盐治疗、骨髓移植或EPH抑制剂进行体内研究，随后在患者来源的异种移植（PDX）小鼠模型中探索其临床治疗价值。
离体研究表明，关键CTS分子的CRD促进了肝转移中生态位的生长。体外研究表明，表达EFNB2的TAM与表达EPHB2的肿瘤细胞相互作用，导致CRD和下游信号激活。潜在机制是转移生态位中Warburg效应的增强。
总体而言，我们旨在揭示TAM诱导CRD促进GC肝转移的机制，并为治疗策略提供新思路。
