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CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. An...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055394/ https://www.ncbi.nlm.nih.gov/pubmed/36993615 http://dx.doi.org/10.1101/2023.03.23.533976 |
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author | Zou, Gengyi Huang, Yuanjian Zhang, Shengzhe Ko, Kyung-Pil Kim, Bongjun Zhang, Jie Venkatesan, Vishwa Pizzi, Melissa P. Fan, Yibo Jun, Sohee Niu, Na Wang, Huamin Song, Shumei Ajani, Jaffer A. Park, Jae-Il |
author_facet | Zou, Gengyi Huang, Yuanjian Zhang, Shengzhe Ko, Kyung-Pil Kim, Bongjun Zhang, Jie Venkatesan, Vishwa Pizzi, Melissa P. Fan, Yibo Jun, Sohee Niu, Na Wang, Huamin Song, Shumei Ajani, Jaffer A. Park, Jae-Il |
author_sort | Zou, Gengyi |
collection | PubMed |
description | Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. 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), Kras(G12D), Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to Kras(G12D), 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. |
format | Online Article Text |
id | pubmed-10055394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-100553942023-03-30 CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion Zou, Gengyi Huang, Yuanjian Zhang, Shengzhe Ko, Kyung-Pil Kim, Bongjun Zhang, Jie Venkatesan, Vishwa Pizzi, Melissa P. Fan, Yibo Jun, Sohee Niu, Na Wang, Huamin Song, Shumei Ajani, Jaffer A. Park, Jae-Il bioRxiv Article Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. 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), Kras(G12D), Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to Kras(G12D), 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. Cold Spring Harbor Laboratory 2023-10-11 /pmc/articles/PMC10055394/ /pubmed/36993615 http://dx.doi.org/10.1101/2023.03.23.533976 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Zou, Gengyi Huang, Yuanjian Zhang, Shengzhe Ko, Kyung-Pil Kim, Bongjun Zhang, Jie Venkatesan, Vishwa Pizzi, Melissa P. Fan, Yibo Jun, Sohee Niu, Na Wang, Huamin Song, Shumei Ajani, Jaffer A. Park, Jae-Il CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title | CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title_full | CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title_fullStr | CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title_full_unstemmed | CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title_short | CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
title_sort | cdh1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055394/ https://www.ncbi.nlm.nih.gov/pubmed/36993615 http://dx.doi.org/10.1101/2023.03.23.533976 |
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