Modeling, dissecting, and subtyping of E-Cadherin inactivation-associated diffuse-type gastric adenocarcinoma

Diffuse-type gastric adenocarcinoma (DGAC) is lethal cancer often diagnosed late and resistant to therapeutics. Although hereditary DGAC is mainly characterized by mutations in the CDH1 gene encoding E-cadherin, the impact of E-cadherin inactivation on sporadic DGAC tumorigenesis remains elusive. We found that CDH1 inactivation occurs only subset of DGAC patient tumors. Unsupervised clustering of single-cell transcriptomes of DGAC patient tumors identified two subtypes of DGACs: DGAC1 and DGAC2. The DGAC1 is mainly characterized by CDH1 loss and exhibits distinct molecular signatures and aberrantly activated DGAC-related pathways. Unlike DGAC2 lacking immune cell infiltration in tumors, DGAC1 tumor is enriched with exhausted T cells. To demonstrate the role of CDH1 loss in DGAC tumorigenesis, we established a genetically engineered murine gastric organoid (GOs; Cdh1 knock-out [KO], KrasG12D, Trp53 KO [EKP]) model recapitulating human DGAC. In conjunction with KrasG12D, Trp53 KO (KP), Cdh1 KO is sufficient to induce aberrant cell plasticity, hyperplasia, accelerated tumorigenesis, and immune evasion. Additionally, EZH2 was identified as a key regulon promoting CDH1 loss-associated DGAC tumorigenesis. These findings underscore the significance of comprehending the molecular heterogeneity of DGAC and its potential implication for personalized medicine to DGAC patients with CDH1 inactivation. ### Competing Interest Statement The authors have declared no competing interest.