The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis
Abstract Background The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04433-8 |
| _version_ | 1827708683761483776 |
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| author | Adrian Georg Simon Su Ir Lyu Mark Laible Stefan Wöll Özlem Türeci Uğur Şahin Hakan Alakus Luca Fahrig Thomas Zander Reinhard Buettner Christiane Josephine Bruns Wolfgang Schroeder Florian Gebauer Alexander Quaas |
| author_facet | Adrian Georg Simon Su Ir Lyu Mark Laible Stefan Wöll Özlem Türeci Uğur Şahin Hakan Alakus Luca Fahrig Thomas Zander Reinhard Buettner Christiane Josephine Bruns Wolfgang Schroeder Florian Gebauer Alexander Quaas |
| author_sort | Adrian Georg Simon |
| collection | DOAJ |
| description | Abstract Background The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort. Methods RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS). Results EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028). Conclusions High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell–matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC. |
| first_indexed | 2024-03-10T17:08:59Z |
| format | Article |
| id | doaj.art-955b99c2c4e6441e84f326d2f0b2a4bd |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-10T17:08:59Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-955b99c2c4e6441e84f326d2f0b2a4bd2023-11-20T10:43:57ZengBMCJournal of Translational Medicine1479-58762023-08-0121111610.1186/s12967-023-04433-8The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosisAdrian Georg Simon0Su Ir Lyu1Mark Laible2Stefan Wöll3Özlem Türeci4Uğur Şahin5Hakan Alakus6Luca Fahrig7Thomas Zander8Reinhard Buettner9Christiane Josephine Bruns10Wolfgang Schroeder11Florian Gebauer12Alexander Quaas13Institute of Pathology, University Hospital Cologne, Medical Faculty, University of CologneInstitute of Pathology, University Hospital Cologne, Medical Faculty, University of CologneBioNTech SEBioNTech SEBioNTech SEBioNTech SEDepartment of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of CologneDepartment of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of CologneDepartment of Internal Medicine I, University Hospital Cologne, Medical Faculty, University of CologneInstitute of Pathology, University Hospital Cologne, Medical Faculty, University of CologneDepartment of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of CologneDepartment of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of CologneDepartment of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of CologneInstitute of Pathology, University Hospital Cologne, Medical Faculty, University of CologneAbstract Background The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort. Methods RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS). Results EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028). Conclusions High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell–matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.https://doi.org/10.1186/s12967-023-04433-8AdenocarcinomaCAR T-cell therapyImmunotherapyClaudinCLDN6Tight junctions |
| spellingShingle | Adrian Georg Simon Su Ir Lyu Mark Laible Stefan Wöll Özlem Türeci Uğur Şahin Hakan Alakus Luca Fahrig Thomas Zander Reinhard Buettner Christiane Josephine Bruns Wolfgang Schroeder Florian Gebauer Alexander Quaas The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis Journal of Translational Medicine Adenocarcinoma CAR T-cell therapy Immunotherapy Claudin CLDN6 Tight junctions |
| title | The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| title_full | The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| title_fullStr | The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| title_full_unstemmed | The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| title_short | The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| title_sort | tight junction protein claudin 6 is a potential target for patient individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis |
| topic | Adenocarcinoma CAR T-cell therapy Immunotherapy Claudin CLDN6 Tight junctions |
| url | https://doi.org/10.1186/s12967-023-04433-8 |
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