Abstract 490P
Background
Gastric cancer (GC) is a common cancer, and due to challenges associated with early diagnosis, the prognostic outlook for gastric cancer is often poorer. Endothelial cell-specific molecule 1 (ESM1), a secreted glycoprotein, exhibits elevated levels in various cancers. However, its specific role in GC remains elusive.
Methods
Publicly available datasets analysis and Kaplan-Meier survival analyses were performed to reveal the expression and clinical relevance of ESM1 in GC. In vitro experiments included colony formation and transwell assays to evaluate cell proliferation and motility. Mechanistic investigations involved dot blot, Western blot, immunofluorescence, immunohistochemistry staining, as well as knockdown and overexpression experiments using shRNA and DNA plasmid transfection techniques in cell lines and patient-derived organoids (PDOs). Furthermore, we employed an in vivo xenograft model to validate our findings.
Results
Independent patient cohorts revealed a strong correlation between elevated ESM1 expression and a poorer prognosis for GC patients. ESM1 positively correlated with the proliferation, migration, and anoikis resistance of GC cell lines, as well as tumor growth in PDOs and in vivo xenograft models of GC cells. Mechanistically, the presence of ESM1 triggered epithelial-mesenchymal transition (EMT) by enhancing EGFR/HER3 association and activating the EGFR/HER3-Akt pathway in GC. In addition, ESM1 highly cooperated with ANGPT2 and interplayed with Akt to induce EMT and cancer progression. We furthermore demonstrated that secreted characteristic of ESM1 is critical for ESM1-induced the aforementioned EGFR/HER3-Akt/ANGPT2 signal, EMT, and tumor growth ability in PDOs and xenograft model. The patients with high levels of both ESM1 and ANGPT2 had the poorest prognosis. Additionally, therapeutic peptides targeting ESM1 effectively suppressed the activation of this signaling pathway and inhibited GC cell migration.
Conclusions
Collectively, ESM1 plays an oncogenic role in GC by activating EGFR/HER3-Akt/ANGPT2 pathway and might be a novel promising therapeutic target for GC.
Legal entity responsible for the study
The authors.
Funding
National Science and Technology Council, Taiwan, ROC.
Disclosure
All authors have declared no conflicts of interest.