Abstract
Inorganic arsenic (iAs) causes cancer by initiating dynamic transitions between epithelial and mesenchymal cell phenotypes. These transitions transform normal cells into cancerous cells, and cancerous cells into metastatic cells. Most in vitro models assume that transitions between states are binary and complete, and do not consider the possibility that intermediate, stable cellular states might exist. In this paper, we describe a new, two-hit in vitro model of iAs-induced carcinogenesis that extends to 28 weeks of iAs exposure. Through week 17, the model faithfully recapitulates known and expected phenotypic, genetic, and epigenetic characteristics of iAs-induced carcinogenesis. By 28 weeks, however, exposed cells exhibit stable, intermediate phenotypes and epigenetic properties, and key transcription factor promoters (SNAI1, ZEB1) enter an epigenetically poised or bivalent state. These data suggest that key epigenetic transitions and cellular states exist during iAs-induced epithelial-to-mesenchymal transition (EMT), and that it is important for our in vitro models to encapsulate all aspects of EMT and the mesenchymal-to-epithelial transition (MET). In so doing, and by understanding the epigenetic systems controlling these transitions, we might find new, unexpected opportunities for developing targeted, cell state-specific therapeutics.
Document Type
Article
Publication Date
4-2024
Digital Object Identifier (DOI)
10.1016/j.envpol.2024.123586
Funding Information
National Science Foundation Arctic Social Science Program NSF/MCB 151798 National Science Foundation Arctic Social Science Program National Science Foundation’s Division of Molecular and Cellular Biosciences 016515 National Science Foundation’s Division of Molecular and Cellular Biosciences National Institutes of Health (NIH) R01 ES034253, R01 ES024478 National Institutes of Health (NIH)
Related Content
© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/)
Repository Citation
Rea, Matthew; Kimmerer, Greg; Mittendorf, Shania; Xiong, Xiaopeng; Green, Megan; Chandler, Darrell; Saintilnord, Wesley; Blackburn, Jessica; Gao, Tianyan; and Fondufe-Mittendorf, Yvonne N., "A dynamic model of inorganic arsenic-induced carcinogenesis reveals an epigenetic mechanism for epithelial–mesenchymal plasticity" (2024). Markey Cancer Center Faculty Publications. 180.
https://uknowledge.uky.edu/markey_facpub/180
