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Matriptase-dependent epidermal pre-neoplasm in zebrafish embryos caused by a combination of hypotonic stress and epithelial polarity defects

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posted on 2023-12-18, 23:59 authored by Julia Hatzold, Verena Nett, Stephanie Brantsch, Jin-Li Zhang, Joy Armistead, Heike Wessendorf, Rebecca StephensRebecca Stephens, Patrick HumbertPatrick Humbert, Sandra Iden, Matthias Hammerschmidt
Aberrantly up-regulated activity of the type II transmembrane protease Matriptase-1 has been associated with the development and progression of a range of epithelial-derived carcinomas, and a variety of signaling pathways can mediate Matriptase-dependent tumorigenic events. During mammalian carcinogenesis, gain of Matriptase activity often results from imbalanced ratios between Matriptase and its cognate transmembrane inhibitor Hai1. Similarly, in zebrafish, unrestrained Matriptase activity due to loss of hai1a results in epidermal pre-neoplasms already during embryogenesis. Here, based on our former findings of a similar tumor-suppressive role for the Na+/K+-pump beta subunit ATP1b1a, we identify epithelial polarity defects and systemic hypotonic stress as another mode of aberrant Matriptase activation in the embryonic zebrafish epidermis in vivo. In this case, however, a different oncogenic pathway is activated which contains PI3K, AKT and NFkB, rather than EGFR and PLD (as in hai1a mutants). Strikingly, epidermal pre-neoplasm is only induced when epithelial polarity defects in keratinocytes (leading to disturbed Matriptase subcellular localization) occur in combination with systemic hypotonic stress (leading to increased proteolytic activity of Matriptase). A similar combinatorial effect of hypotonicity and loss of epithelial polarity was also obtained for the activity levels of Matriptase-1 in human MCF-10A epithelial breast cells. Together, this is in line with the multi-factor concept of carcinogenesis, with the notion that such factors can even branch off from one and the same initiator (here ATP1a1b) and can converge again at the level of one and the same mediator (here Matriptase). In sum, our data point to tonicity and epithelial cell polarity as evolutionarily conserved regulators of Matriptase activity that upon de-regulation can constitute an alternative mode of Matriptase-dependent carcinogenesis in vivo.


Work in the laboratory of MH was supported by the German Research Foundation (DFG;; Research Grant project No. 453407124 and SFB 829, including the salary for Julia Hatzold) and the US National Institute of General Medical Sciences (; GM63904), work in the laboratory of SI by the DFG (; Research Grant project No. 273723548 and SFB 1027, project A12, including the salary for Verena Nett), POH was supported from Grant APP1160025 and a Senior Research Fellowship APP1079133 for Rebecca Stephens from the Australian National Health and Medical Research Council (


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PLoS Genetics





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Public Library of Science



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© 2023 Hatzold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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