2200 København N.
The Vogel Group explores the interplay between the serine proteases matriptase and prostasin, and the inhibitors/ally proteins HAI-1 and HAI-2, to design new treatment(s) for cancer patients.
Primary fields of research
Is a cure for cancer within reach?
Research in mice has shown that over-expression of the transmembrane serine protease, matriptase, single-handedly causes tumors with high efficiency . Matriptase is located on the basolateral plasma membrane of all epithelial cells [2, 3] and all epithelial cell-derived cancers , and catalyzes the conversion of signal molecules, leading to the activation of signal transduction pathways [5, 6]. Under normal conditions, matriptase is kept under strict control by the serine protease inhibitors HAI-1 and HAI-2 [7, 8]. Up to 90% of cancers are believed to be of epithelial origin, and most display dysregulated expression of matriptase, HAIs, or both . Indicating that the matriptase regulatory system is involved in most epithelial-derived cancers.
Mouse model studies have shown that high expression of matriptase leads to malignant cancer that can be prevented by simultaneous over-expression of either HAI-1 or HAI-2 [1, 9]. In 2015 it was shown that over-expression of HAI-2 caused regression and remission of individual, established, and epithelial-derived malignant tumors in a mouse model . Similar results have also been obtained using human prostate cancer cells in a mouse model . These studies suggest that sufficient levels of HAIs can reverse carcinogenesis and treat epithelial-derived malignant cancers.
It appears that activation of matriptase is necessary for the development of cancer, as over-expression of a matriptase protein that can be activated, leads to cancer , whereas over-expression of zymogen-locked matriptase does not . Matriptase activation can be auto-catalyzed by the active zymogen form of another matriptase or by another activated matriptase . The protease can also be activated by the active zymogen form of the serine protease prostasin, or by activated prostasin . All four activators can be inhibited by HAI-1 and HAI-2.
In addition to being serine protease inhibitors, HAI-1 and HAI-2 are also ally proteins, acting on the newly synthesized zymogen matriptase, preventing its post-translational degradation by an unknown mechanism [14-16]. At present, it is unclear whether it is the inhibitory function of the HAIs, their ally function, or both combined that can cause carcinogenesis to reverse and tumors to regress.
The goal of the Vogel laboratory is to provide a basic understanding of the interplay between matriptase, prostasin, HAI-1, and HAI-2 to design treatment(s) for cancer and other diseases.
A treatment for established malignant tumors
Mouse model studies have shown that high expression of Matriptase leads to malignant cancer and that this can be prevented by simultaneous over-expression of either HAI-1 or HAI-2 [1, 2]. Similar results have also been obtained using human prostate cancer cells in a mouse model . These studies suggest that sufficient levels of HAIs can reverse carcinogenesis and treat epithelial-derived malignant cancers. Unfortunately, HAIs are membrane-bound proteins and cannot be used clinically.
Inhibitors of the Matriptase-activators are likely to be found within the human genome, as they are still a highly understudied group of proteins and serine protease inhibitors generally display high promiscuity, which is reflected in the HAI’s ability to inhibit all four Matriptase-activators in addition to several other known serine proteases.
Our laboratory has, as the only one in the world, established several assays detecting inhibition of the activators of matriptase, allowing us to screen for inhibitors better suited for clinical use.
The HAIs unique ally protein function may also be involved in reversing carcinogenesis. Therefore, we simultaneously investigate the HAIs ally protein mechanism.
Epithelial-derived cancers are sometimes detected late or located in places difficult to reach with conventional treatments, like surgery and chemotherapy. Cancer therapy based on a systemic application of a safe protease inhibitor will therefore be a huge advantage and could save many lives.
Matriptase variants cause autosomal, recessive, congenital, ichthyosis 11
Ichthyosis is a common disease that causes "fish-scale" like skin with poor treatment options. The molecular mechanisms behind ichthyosis are not understood, but variants in several genes, including the filaggrin gene, cause ichthyosis.
Matriptase knock-out mice  and prostasin knock-out mice  both lack profilaggrin processing, which has also been observed in a patient with ichthyosis caused by a matriptase variant . This strongly suggests that matriptase, prostasin, and filaggrin are part of the same enzymatic cascade, which causes ichthyosis when its function is abrogated.
Multiple variants in the ST14 gene encoding the serine protease matriptase lead to a type of ichthyosis called Autosomal, Recessive, Congenital, Ichthyosis 11 (ARCI11). We are currently investigating the proteolytic properties of the ARCI11-causing matriptase variants.
The frequency of ARCI11 is elusive at present. We have genetic material available to do a systematic search for other ARCI11-causing variants of matriptase. We plan to screen this material for new variants and estimate the frequency of both new and known ARCI11 variants. We believe that information about the matriptase variants will lead to a better understanding of ichthyosis and improve treatment options.
- Adam Frederik Sander Pedersen, University of Copenhagen, Copenhagen, Denmark
- Chen-Yong Lin, University of Maryland, Maryland, USA
- Christine Schar, University of Aarhus, Aarhus, Denmark
- Hans Eiberg, University of Copenhagen, Copenhagen, Denmark
- Hiroaki Kataoka, University of Miyazaki, Miyazaki, Japan
- Jan K. Jensen, University of Aarhus, Aarhus, Denmark
- Lars Ellgaard, University of Copenhagen, Copenhagen, Denmark
- Makiko Kawaguchi, University of Miyazaki, Miyazaki, Japan
- Roman Szabo, NIH, Bethesda, Maryland, USA
- Thomas H. Bugge, NIH, Bethesda, Maryland, USA