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E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming
Gengyi Zou1, Yuanjian Huang1,2, Shengzhe Zhang1
1Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Journal of Experimental Medicine
|February 27, 2024
Summary
Diffuse-type gastric adenocarcinoma (DGAC) subtypes were identified, with CDH1 loss linked to distinct molecular features and immune evasion. This discovery offers new avenues for personalized treatment strategies in gastric cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Diffuse-type gastric adenocarcinoma (DGAC) is aggressive and treatment-resistant.
- The role of CDH1/E-cadherin inactivation in sporadic DGAC is not well understood.
- Hereditary DGAC is associated with CDH1 mutations.
Purpose of the Study:
- To investigate the role of CDH1 inactivation in sporadic DGAC.
- To identify molecular subtypes of DGAC.
- To explore therapeutic targets for DGAC.
Main Methods:
- Single-cell transcriptomic analysis of malignant ascites.
- Genetically engineered murine gastric organoid models.
- Analysis of CDH1 and EZH2 expression and function.
Main Results:
- Two DGAC subtypes identified: DGAC1 (CDH1 loss) and DGAC2 (immune-evasive).
- DGAC1 exhibits unique molecular signatures and abundant exhausted T cells.
- Cdh1 knockout accelerates gastric tumorigenesis and immune evasion in murine models.
- EZH2 identified as a mediator in CDH1 loss-associated DGAC.
Conclusions:
- DGAC is molecularly diverse, with CDH1 inactivation defining a distinct subtype.
- CDH1 loss promotes tumorigenesis and immune evasion in DGAC.
- Targeting EZH2 or leveraging CDH1 status may enable personalized DGAC treatments.
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