Cell division‐dependent dissemination following E‐cadherin loss underlies initiation of diffuse‐type gastric cancer

Abstract Loss of the cell–cell adhesion protein E‐cadherin underlies the development of diffuse‐type gastric cancer (DGC), which is characterized by the gradual accumulation of tumor cells originating from the gastric epithelium in the surrounding stroma. How E‐cadherin deficiency drives DGC formation remains elusive. Therefore, we investigated the consequences of E‐cadherin loss on gastric epithelial organization utilizing a human gastric organoid model and histological analyses of early‐stage DGC lesions. E‐cadherin depletion from gastric organoids recapitulates DGC initiation, with progressive loss of a single‐layered architecture and detachment of individual cells. We found that E‐cadherin deficiency in gastric epithelia does not lead to a general loss of epithelial cohesion but disrupts the spindle orientation machinery. This leads to a loss of planar cell division orientation and, consequently, daughter cells are positioned outside of the gastric epithelial layer. Although basally delaminated cells fail to detach and instead reintegrate into the epithelium, apically mispositioned daughter cells can trigger the gradual loss of the single‐layered epithelial architecture. This impaired architecture hampers reintegration of mispositioned daughter cells and enables basally delaminated cells to disseminate into the surrounding matrix. Taken together, our findings describe how E‐cadherin deficiency disrupts gastric epithelial architecture through displacement of dividing cells and provide new insights in the onset of DGC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.