Matthias Hammerschmidt - A 4

The multiple facets of the type II transmembrane serine protease ST14 and hypotonic stress during carcinogenesis in fish and mammals

Abstract

The type II transmembrane serine protease (TTSP) matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This dual role is evident in the embryonic phenotype of zebrafish loss-of-function mutants in hai1a, which encodes the cognate inhibitor of matriptase. Mutants display epidermal hyperplasia and early steps of basal invasiveness (oncogenic), but also apical cell extrusions (tumor-suppressive), both of which depend on the matriptase mediators EGFR and phopholipase D. Accordingly, their chemical inhibition leads to transient alleviation of epidermal pathology, but a later increase in epidermal masses, possibly resulting in long-term malignancy / cancer relapse. Further analyses revealed the involvement of hypotonic stress, TA isoforms of p53 and Notch in matriptase-dependent epidermal tumorigenesis in zebrafish embryos. We will elucidate the functional connection between these players, and will search for combinations of small molecule antagonists / agonists dissecting the oncogenic and tumor-suppressive effects, including analyses of metastasis via live imaging in treated mutants. Furthermore, identified principles and treatments will be tested in adult zebrafish models of matriptase-dependent and –independent epidermal carcinomas that we have created during the current funding period, as well as in models of mammalian non-small cell lung carcinomas, which display striking similarities to epidermal carcinomas in zebrafish embryos.

Clinical/medical relevance and sustainability in disease understanding

The dual role of matriptase as oncogene and tumor suppressor has important implications for human disease, as current therapeutic strategies are likely to affect both. The zebrafish allows high throughput drug discovery and molecular networks elucidation in embryos, as well as live imaging of cancer formation and metastasis in adults. This study will contribute to the imperative need for tailoring treatments to the molecular context, and will validate alternatives for combating matriptase-dependent and independent carcinogenesis in human.


Prof. Dr. rer. nat. Matthias Hammerschmidt

Institute for Zoology

Prof. Dr. rer. nat. Matthias Hammerschmidt

Principal Investigator A 4
Executive Board Member

mhammers@uni-koeln.de

Work +49 221 470 5665

Fax (Work) +49 221 470 5184

Institute for Developmental Biology
Zülpicher Str. 47b
50674 Cologne

http://www.uni-koeln.de/math-nat-fak/ebio/de/Forschung/Hammerschmidt/hammerschmidt.html

Publications - Matthias Hammerschmidt

Link to PubMed