OA02.6. Endogenous Interstrand Crosslinks Drive Esophageal Carcinogenesis in Three-Dimensional Organoid Models

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ID: 325945
2026
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Ranked #25 of 453 articles by views in diseases of the esophagus : official journal of the international society for diseases of the esophagus

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Abstract
Abstract Topic Esophageal Cancer: Esophageal Carcinogenesis Background Three-dimensional (3D) organoids are powerful research tools that recapitulate tissue architecture and gene expression, enabling the observation of morphological changes during carcinogenesis. This study aimed to elucidate unknown mechanisms of esophageal carcinogenesis through the analysis of organoids derived from normal and cancer tissues. Methods Murine esophageal organoids (MEOs) were established from mice treated with the chemical carcinogen 4NQO to generate ESCC organoids, whereas organoids derived from untreated mice served as normal controls. To model Fanconi anemia (FA)-associated defects in interstrand crosslink (ICL) repair, MEOs were generated from Fanca-/-, Fancc-/-, Fanct-/- mice, with wild-type MEOs served as controls. In addition, esophageal epithelial tissues from patients with FA were used to establish patient-derived organoids (PDOs), enabling translational comparison between murine and human models. To further investigate the contribution of endogenous formaldehyde metabolism to esophageal carcinogenesis, CRISPR-Cas9-mediated depletion of Adh5, a key enzyme responsible for formaldehyde detoxification, was performed in organoids derived from Aldh2*2 mutant mice. Organoids were characterized by morphological assessment, immunostaining and gene expression analyses. Functional assay evaluated sensitivity to ICL-inducing agents, including aldehydes, mitomycin C and SJG-136, as well as tumorigenic potential. ICL accumulation and DNA damage were quantified using modified comet assays. Results Cancer-derived organoids established from 4NQO-treated mice exhibited increased DNA damage and activation of multiple DNA repair pathways compared with normal epithelial organoids. Among these pathways, the FA pathway, which is responsible for interstrand crosslink (ICL) repair, was the most prominently activated. Normal epithelial organoids derived from FA gene-deficient mice showed significant accumulation of ICLs and, upon serial passaging, developed morphological alterations and differentiation abnormalities resembling those observed in cancer-derived organoids. Similar phenotypic changes were also observed in organoids generated from FA patients, supporting the clinical relevance of the model. Furthermore, Adh5 knockout organoids demonstrated accumulation of formaldehyde-derived DNA adducts and ICLs, indicating impaired detoxification of endogenous formaldehyde. These changes were accompanied by morphological features similar to those observed in FA-deficient organoids, suggesting the endogenous aldehyde-induced DNA damage contributes to genomic instability and epithelial transformation. Conclusion Cancer-derived organoids demonstrated accumulation of ICLs and activation of the FA pathway. FA-deficient organoids exhibited morphological changes resembling those seen in cancer, suggesting that accumulation of endogenous ICLs contributes to carcinogenesis. Similarly, Adh5 knockout organoids displayed comparable phenotypic changes, implicating endogenous formaldehyde-induced DNA damage in tumor development. These findings suggest that endogenous formaldehyde plays a role in carcinogenesis and may represent a potential target for cancer prevention.
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Authors Wataru Hirose, Samuel Flashner, Debora Cavero Moreno, Kento Kawasaki, Cecilia Martin, Hiroshi Nakagawa
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Journal diseases of the esophagus : official journal of the international society for diseases of the esophagus
Year 2026
DOI
10.1093/dote/doag077.018
URL
https://academic.oup.com/dote/article-pdf/39/Supplement_1/doag077.018/70760884/doag077.018.pdf
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