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The University of Texas MD Anderson Cancer Center

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J. Exp. Med., February 27 2024, 221 (4) e20230561 | https://doi.org/10.1084/jem.20230561 E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming

Gengyi Zou^1*, Yuanjian Huang^1,2*, Shengzhe Zhang¹, Kyung-Pil Ko¹, Bongjun Kim¹, Jie Zhang¹, Vishwa Venkatesan¹, Melissa P Pizzi³, Yibo Fan³, Sohee Jun¹, Na Niu⁴, Huamin Wang⁵, Shumei Song³, Jaffer A Ajani³, Jae-Il Park^1,6,7

¹Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

²Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

³Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

⁴Department of Pathology, Yale School of Medicine, New Haven, CT, USA.

⁵Division of Pathology/Lab Medicine, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

⁶Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.

⁷Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.

^*G. Zou and Y. Huang contributed equally to this paper

Correspondence to Jae-Il Park

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.

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형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-29)
연구진국외 연구진
분야 의약학 > 분자세포의학

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