CDH1 loss defines distinct diffuse-gastric cancer subtype with T cell exhaustion and EZH2 regulon activation
Introduction
Diffuse-type gastric adenocarcinoma (DGAC) is deadly cancer that is often diagnosed late and is resistant to therapies. In this study, we aimed to investigate the impact of CDH1 inactivation on sporadic DGAC tumorigenesis and to identify molecular signatures associated with DGAC subtypes.
Methods
We performed unsupervised clustering of single-cell transcriptomes from DGAC patient tumors and tumor niches and established a genetically engineered murine gastric organoid model to study the impact of CDH1 loss on DGAC tumorigenesis. We also performed single-cell RNA sequencing (scRNA-seq)-based functional assays and molecular analysis to identify key regulons promoting CDH1 loss-associated DGAC tumorigenesis.
Results
We identified two subtypes of DGAC: DGAC1 and DGAC2. DGAC1 is characterized by CDH1 loss and exhausted T cells. In contrast, DGAC2 lacks immune cell infiltration in tumors. The genetically engineered murine gastric organoid model (Cdh1 knock-out [KO], KrasG12D, Trp53 KO [EKP]) recapitulated the DGAC1 subtype, with CDH1 KO inducing aberrant cell plasticity, hyperplasia, accelerated tumorigenesis, and immune evasion. EZH2 was identified as a key regulon promoting CDH1 loss-associated DGAC tumorigenesis.
Conclusion
We underscore the significance of comprehending the molecular heterogeneity of DGAC and the potential implication for DGAC patient stratification by CDH1 status. The findings provide new insight into the mechanisms underlying CDH1 loss-associated DGAC tumorigenesis and immune evasion.