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bioRxiv · 10.1101/2023.04.03.534985

ALDH2 dysfunction accelerates ESCC pathogenesis

Flashner, S.·Shimonosono, M.·Matsuura, N.·Ohashi, S.·Klein-Szanto, A. J.·Diehl, J. A.·Chen, C.-H.·Nakagawa, H.
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Abstract

The alcohol metabolite acetaldehyde is a potent human carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulates and causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Chronic alcohol users with heterozygous ALDH2*2 display an increased risk for the development of esophageal squamous cell carcinoma (ESCC) and other alcohol-related cancers. However, how ALDH2 influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure results in increased organoid formation and tumor growth concurrent with increased reactive oxygen species (ROS), increased DNA damage, and the enrichment of putative cancer stem cells (CSCs) characterized by high CD44 expression. Pharmacological activation of ALDH2 function by Alda-1 inhibits this phenotype, indicating that acetaldehyde is the primary driver of these changes. ALDH2 dysfunction also affects response to a commonly used chemotherapy for the treatment of ESCC. We find that Aldh2 dysfunction facilitated enrichment of CSCs following cisplatin-induced cell death and oxidative stress in murine organoids. Together, these data provide evidence that alcohol exposure, results in more aggressive tumors through enrichment of CSCs, which is augmented by ALDH2 dysfunction.

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Flashner, S., Shimonosono, M., Matsuura, N., Ohashi, S., Klein-Szanto, A. J., Diehl, J. A., Chen, C.-H., Nakagawa, H.. 2023-04-05. ALDH2 dysfunction accelerates ESCC pathogenesis. https://doi.org/10.1101/2023.04.03.534985

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