PD Dr. rer. nat. Martin Götte
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martingotte@uni-muenster.de http://klinikum.uni-muenster.de/index.php?id=3797 |
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The research group of PD Dr. Martin Götte has a long-standing interest in analysing the molecular role of proteoglycans and glycosaminoglycans in the pathogenesis of malignant and inflammatory diseases. In previous work, we could demonstrate that dysregulated expression of the heparan sulfate proteoglycan Syndecan-1 is of predictive value for the outcome of neoadjuvant chemotherapy of breast cancer, and that its expression is associated with angiogenesis and lymphangiogenesis in early stages of breast cancer. Using in vitro overexpression and siRNA knockdown and microRNA transfection approaches assisted by Affymetrix gene array technology in human breast cancer cell lines, we demonstrated that Syndecan-1 is a novel target of prometastatic microRNAs, and that dysregulation of Syndecan-1 affects numerous molecular processes contributing to breast cancer pathogenesis. Heparan-sulfate dependent modulation of multiple receptor tyrosine kinase signalling as well as integrin-dependent pathways, dysregulated expression of homotypic cell adhesion molecules and altered expression and activity of MMPs were identified as molecular aspects of Syndecan-1 function in the pathogenesis and progression of breast cancer.
Using a complementary ectopic expression approach of enzymes involved in heparan sulfate biosynthesis, we could identify a specific role for 3-O-sulfated heparan sulfate residues in mediating breast cancer cell invasiveness via modulation of a TCF4-dependent signal transduction pathway. A similar experimental approach revealed that 6-O-sulfated heparan sulfate residues may affect the invasive behaviour of aggressive breast cancer cell lines via a different molecular mechanism, which is currently being explored.
A second area of intense research is the elucidation of the role of the heparan sulfate proteoglycan syndecan-1 in inflammation. Investigating syndecan-1-deficient knockout mice, we demonstrated that lack of syndecan-1 results in increased leukocyte recruitment to the endothelium, and in exaggerated inflammatory responses in several in vivo and in vitro models of inflammation. A heparan sulfate-dependent modulation of integrin-ICAM-1 interactions and dysregulated chemokine function were identified as underlying mechanisms in this process. In a joint effort with the group of PD Dr. Seidler, we are extending this approach to additional proteoglycan knockout mouse models.
The Götte laboratory has extensive experience in training both German and International students, and it relies on an extensive national and international network of collaborators, including researchers in the USA, Singapore, Brazil, Italy, Israel and Sweden. Work in the Götte laboratory has been funded by the EU, the DAAD, the DFG, the GIF, and industry sources.
Expertise offered:
• ectopic overexpression of proteoglycans and glycosaminoglycan biosynthetic enzymes in cell culture models
• in vivo studies on proteoglycan gene knockout mouse models
• analysis of glycan-dependent signal transduction pathways
• siRNA and microRNA transfection approaches of manipulating proteoglycan and glycosyltransferase expression
• real-time PCR and TaqMan low density array analysis of gene and microRNA expression
• proteoglycan and glycosaminoglycan purification and biochemistry
• functional assays of tumor cell behaviour in vitro and in vivo
• all standard molecular biology, cell biology, biochemistry and immunocytochemistry techniques
