胃癌（GC）由于其早期诊断困难和耐药性而构成全球性挑战，因此需要识别早期检测标记物并了解有效的GC治疗的致癌途径。内皮细胞特异性分子 1 (ESM1) 是一种分泌性糖蛋白，在多种癌症中表达升高，但其在 GC 中的作用仍存在争议。在我们的研究中，ESM1 在 GC 组织中升高，其浓度与独立队列中的进展和较差的患者预后相关。从功能上讲，ESM1 表达促进 GC 细胞的增殖、失巢凋亡抵抗和运动，以及 PDO 和 GC 异种移植模型中的肿瘤生长。从机制上讲，ESM1 表达通过增强表皮生长因子受体 (EGFR)/人 EGFR 3 (HER3) 关联并激活 EGFR/HER3-Akt 通路，触发 GC 细胞的上皮间质转化 (EMT)。此外，血管生成素-2 (ANGPT2) 被发现与 ESM1 高度相关，并与 Akt 相互作用，诱导 EMT 和癌症进展。使用信号肽缺失突变体 (ESM1-19del) 表明，ESM1 的分泌形式通过激活 EGFR/HER3-Akt/ANGPT2 途径促进 EMT，对其促肿瘤作用至关重要。 ESM1 和 ANGPT2 水平较高的患者预后最差。此外，治疗肽成功抑制了 ESM1 对上述信号的诱导和 GC 细胞的运动。 ESM1 在 GC 中的致癌作用涉及激活 EGFR/HER3-Akt/ANGPT2 通路，为 GC 提供了潜在的治疗靶点。© 作者。

Gastric cancer (GC) poses global challenges due to its difficult early diagnosis and drug resistance, necessitating the identification of early detection markers and understanding of oncogenic pathways for effective GC therapy. Endothelial cell-specific molecule 1 (ESM1), a secreted glycoprotein, is elevated in various cancers, but its role in GC remains controversial. In our study, ESM1 was elevated in GC tissues, and its concentration was correlated with progression and poorer patient prognosis in independent cohorts. Functionally, ESM1 expression promoted proliferation, anoikis resistance, and motility of GC cells, as well as tumor growth in PDOs and in GC xenograft models. Mechanistically, ESM1 expression triggered the epithelial-to-mesenchymal transition (EMT) of GC cells by enhancing epidermal growth factor receptor (EGFR)/human EGFR 3 (HER3) association and activating the EGFR/HER3-Akt pathway. Additionally, angiopoietin-2 (ANGPT2) was found to be highly correlated with ESM1 and interplayed with Akt to induce the EMT and cancer progression. Use of a signal peptide deletion mutant (ESM1-19del) showed that the secreted form of ESM1 is crucial for its protumorigenic effects by activating the EGFR/HER3-Akt/ANGPT2 pathway to promote the EMT. Patients with high levels of both ESM1 and ANGPT2 had the poorest prognoses. Furthermore, therapeutic peptides successfully inhibited ESM1's induction of the aforementioned signals and motility of GC cells. ESM1's oncogenic role in GC involves activating the EGFR/HER3-Akt/ANGPT2 pathway, presenting a potential therapeutic target for GC.© The author(s).