Oncology

Myeloid‐Derived LGALS9‐P4HB Immune Interaction Promotes Metastasis in Gastric Cancer Through Enhanced Cell Proliferation and Lipid Metabolism

Ethan Littlefield

05 Jul 2025 — 1 min read

PMCID: PMC12176694

PMID: 40534096

DOI: 10.1111/jcmm.70661

Journal: Journal of cellular and molecular medicine

Publication Date: 2025-6-18

Authors: Zhu X, Zhang Y, Yu A, Xiao X

Key Points

Myeloid cell-derived LGALS9 and epithelial cell P4HB interaction is a previously uncharacterized mechanism driving gastric cancer metastasis
Pharmacological P4HB inhibitors (Q3R and BAC) demonstrated ability to suppress metastatic cell proliferation, EMT, and lipid metabolism
Targeting the LGALS9-P4HB interaction represents a promising novel therapeutic strategy for metastatic gastric cancer

Summary

This single-cell transcriptomic study investigated the molecular mechanisms driving gastric cancer metastasis by comprehensively analyzing primary tumors and their liver and lymph node metastases. The research uncovered a novel intercellular communication network involving myeloid cell-derived Galectin-9 (LGALS9) and its receptor P4HB on epithelial cells, which plays a critical role in metastatic progression through enhanced proliferation, epithelial-mesenchymal transition (EMT), and lipid metabolism reprogramming.

The study revealed significant differences in cellular composition between primary and metastatic sites, with notably distinct immune cell proportions. Critically, metastatic epithelial cells demonstrated upregulation of cholesterol metabolism and PPAR signaling pathway genes. Functional experiments confirmed that LGALS9 activation of P4HB promotes cancer cell proliferation and metastatic potential, with pharmacological inhibition of P4HB effectively reversing these pro-metastatic effects, suggesting a potential targeted therapeutic approach for metastatic gastric cancer.

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