E-Cadherin Loss Drives Diffuse-Type Gastric Tumorigenesis via EZH2-Mediated Reprogramming

Authors

Gengyi Zou
Yuanjian Huang
Shengzhe Zhang
Kyung-Pil Ko
Bongjun Kim
Jie Zhang
Vishwa Venkatesan
Melissa P Pizzi
Yibo Fan
Sohee Jun
Na Niu
Huamin Wang
Shumei Song
Jaffer A Ajani
Jae-Il Park

Publication Date

4-1-2024

Journal

Journal of Experimental Medicine

Abstract

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

Keywords

Humans, Animals, Mice, Ascites, Carcinogenesis, Cell Transformation, Neoplastic, Stomach, Cadherins, Enhancer of Zeste Homolog 2 Protein

Comments

Supplementary Materials

Data Availability Statement

PMID: 38411616