EpCAM-dependent membrane mechanics regulate nuclear deformation and promote gastric cancer metastasis.

Diffuse gastric cancer is highly metastatic and lacks effective therapeutic targets. Using membrane proteomics, gastric cancer cell models, biophysical measurements, and in vivo metastasis assays, we identify EpCAM as a regulator of membrane-cytoskeletal mechanics. EpCAM overexpression was associated with reduced apparent plasma membrane tension, ERM-actin remodeling, increased traction forces, and nuclear deformation. Functional perturbation of ezrin and lamin A/C supported the involvement of membrane-cytoskeleton-nucleus mechanical coupling in confined migration. EpCAM knockout or monoclonal antibody blockade reduced tumor invasion and lymph node dissemination in vivo. These findings establish a mechanobiological framework linking EpCAM-dependent membrane mechanics to metastatic behavior and highlight EpCAM-associated mechanical regulation as a potential therapeutic vulnerability in diffuse gastric cancer.