ELFN2 inhibits YAP-driven lymph node metastasis in gastric cancer by blocking PP1A-mediated dephosphorylation

Lymph node metastasis (LNM) is the most frequent metastatic pathway in gastric cancer (GC) and a major determinant of poor prognosis, but the underlying molecular mechanisms remain poorly defined. In this study, we investigated the role of extracellular leucine-rich repeat and fibronectin type III domain-containing protein 2 (ELFN2) in LNM and its therapeutic potential in GC. ELFN2 expression was examined in clinical GC tissues and found to be significantly downregulated in cases with LNM, with low ELFN2 levels correlating with unfavorable patient survival. Mechanistic studies demonstrated that ELFN2 interacts directly with the catalytic subunit alpha of protein phosphatase-1 (PP1A), thereby inhibiting YAP dephosphorylation at Ser127. This regulation promotes YAP nuclear export and functional inactivation. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation, confirming the requirement of PP1A in this process. To further validate the biological significance of ELFN2, we established in vivo models of LNM and peritoneal carcinomatosis, which consistently showed that ELFN2 suppresses metastatic dissemination. Together, our results reveal a novel ELFN2/PP1A/YAP signaling axis that plays a critical role in controlling LNM in GC. Importantly, these findings not only provide new insights into the molecular mechanisms governing GC metastasis but also highlight ELFN2 as a promising biomarker and potential therapeutic target for the management of GC patients at high risk of LNM.