Zhu Xiaobin, Zhang Yating, Yu Aiping, Xiao Xiao
Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
Institute of Health Inspection and Testing, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei, China.
J Cell Mol Med. 2025 Jun;29(12):e70661. doi: 10.1111/jcmm.70661.
Metastasis remains the primary cause of mortality in gastric cancer patients; however, the underlying mechanisms driving this process remain incompletely understood. Here, we performed an integrated single-cell analysis of gastric cancer primary tumours and their corresponding liver and lymph node metastases to identify critical intercellular communication networks driving the metastatic process. Notably, gene expression analysis of metastatic tissues showed significant upregulation of cholesterol metabolism and PPAR signalling pathway (a nuclear receptor-mediated regulatory system that orchestrates lipid metabolism, adipogenesis and energy homeostasis) genes compared to primary tumours. Our analysis revealed that myeloid cell-derived Galectin-9 (LGALS9) and its receptor beta-subunit of prolyl 4-hydroxylase (P4HB) on epithelial cells constitute a previously uncharacterized ligand-receptor interaction involved in gastric cancer metastasis. Functional experiments confirmed that the activation of P4HB by LGALS9 significantly enhanced proliferation, epithelial-mesenchymal transition (EMT) and lipid metabolism in gastric cancer cells, while pharmacological inhibition of P4HB reversed these effects. Collectively, our findings establish the myeloid-derived LGALS9-P4HB interaction as a crucial mediator of gastric cancer metastatic colonisation through modulation of lipid metabolism, suggesting a potential therapeutic target for metastatic gastric cancer.
转移仍然是胃癌患者死亡的主要原因；然而，驱动这一过程的潜在机制仍未完全了解。在此，我们对胃癌原发肿瘤及其相应的肝转移灶和淋巴结转移灶进行了综合单细胞分析，以确定驱动转移过程的关键细胞间通讯网络。值得注意的是，与原发肿瘤相比，转移组织的基因表达分析显示胆固醇代谢和PPAR信号通路（一种协调脂质代谢、脂肪生成和能量稳态的核受体介导的调节系统）相关基因显著上调。我们的分析表明，髓样细胞衍生的半乳糖凝集素-9（LGALS9）及其在上皮细胞上的受体脯氨酰4-羟化酶（P4HB）的β亚基构成了一种先前未被描述的参与胃癌转移的配体-受体相互作用。功能实验证实，LGALS9激活P4HB可显著增强胃癌细胞的增殖、上皮-间质转化（EMT）和脂质代谢，而对P4HB的药理抑制可逆转这些作用。总体而言，我们的研究结果表明，髓样细胞衍生的LGALS9-P4HB相互作用通过调节脂质代谢，是胃癌转移定植的关键介质，提示其可能是转移性胃癌的潜在治疗靶点。
