Our major interest is the interplay between cells and their microenvironment in health and disease. We work to understand the interactions between cells and the extracellular matrix and to utilize this understanding to create novel therapeutic options, particularly in cancer treatment. Our particular focus is receptors and proteolytic enzymes that govern the homeostasis and degradation of collagen, the major protein constituent of higher organisms.
Collagen interactions and turnover
The unique triple helical structure of collagens makes them distinct from most other proteins in terms of molecular recognition and degradation. We work to identify and characterize the ensemble of proteins that direct collagen turnover in normal physiology and pathological conditions. The work includes protein interaction analyses, studies in cell culture and pursuing the findings in mouse model studies, including relevant knock-out mice and cancer models. We have identified a specific endocytic collagen receptor, Endo180/uPARAP, with important functions in fibrosis and cancer invasion. Our current work is focused on this receptor and related proteins, as well as membrane-associated collagenolytic metalloproteases.
Interference with cancer invasion
Based on the understanding of our focus components in cancer invasion, we generate specific model therapeutics for proof-of-concept studies in mouse models. We utilize knock-out mice that lack critical matrix degrading components as host animals for immunization to generate mouse monoclonal antibodies against mouse proteins, including specific “blocking” antibodies. These antibodies are used for specific functional blocking studies in wild type mice in vivo in connection with cancer models.
Antibody against Endo180/uPARAP blocks the uptake and degradation of collagen (green label) in sarcoma cells
Our current projects include:
- Identification of the group of endocytic receptors that function in collagen turnover
- Understanding the endocytic route of collagen degradation
- Studies on matrix-induced changes in cellular gene expression in connection with invasiveness
- Interfering with endocytic receptors and surface-associated proteases in cancer invasion models in mice
- Utilization of Endo180/uPARAP and related receptors for cell specific drug delivery
Madsen, D.H., Engelholm, L.H., Ingvarsen, S., Hillig, T., Wagenaar-Miller, R.A., Kjøller, L., Gårdsvoll, H., Høyer-Hansen, G., Holmbeck, K., Bugge, T.H. and Behrendt, N.
Extracellular collagenases and the endocytic receptor, urokinase plasminogen activator receptor-associated protein/Endo180, cooperate in fibroblast-mediated collagen degradation.
J. Biol. Chem. (2007), 282: 27037-27045. [E-pub 2007, Jul 9].
Wagenaar-Miller, R.A., Engelholm, L.H., Gavard, J., Yamada, S.S., Gutkind, J.S., Behrendt, N., Bugge, T.H. and Holmbeck, K.
Complementary roles of intracellular and pericellular collagen degradation pathways in vivo.
Mol. Cell. Biol. (2007), 27: 6309-6322. [E-pub 2007, Jul 9].
Ingvarsen, S., Madsen, D.H., Hillig, T., Lund, L.R., Holmbeck, K., Behrendt, N. and Engelholm, L.H.
Dimerization of endogenous MT1-MMP is a regulatory step in the activation of the 72 kDa gelatinase MMP-2 on fibroblasts and fibrosarcoma cells.
Biol. Chem. (2008), 389: 943-953.
Hillig, T., Engelholm, L.H., Ingvarsen, S., Madsen, D.H., Gårdsvoll, H., Larsen, J.K., Ploug, M., Danø, K., Kjøller, L. and Behrendt, N.
A composite role of vitronectin and urokinase in the modulation of cell morphology upon expression of the urokinase receptor.
J. Biol. Chem. (2008), 283: 15217-15223. [E-pub 2008, Mar 24].
Lund, I.K., Jögi, A., Rønø, B., Rasch, M.G., Lund, L.R., Almholt, K., Gårdsvoll, H., Behrendt, N., Rømer, J. and Høyer-Hansen, G.
Antibody-mediated targeting of the uPA proteolytic function neutralizes fibrinolysis in vivo.
J. Biol. Chem. (2008), 283: 32506-32515. [E-pub 2008, Sep 17].
Engelholm, L.H., Ingvarsen, S., Jürgensen, H.J., Hillig, T., Madsen, D.H., Nielsen B.S. and Behrendt, N.
The collagen receptor uPARAP/Endo180.
Front. Biosci. (2009), 14: 2103-2114.
Madsen, D.H., Ingvarsen, S., Jürgensen, H.J., Melander, M.C., Kjøller, L., Moyer, A., Honoré, C., Madsen, C.A., Garred, P., Burgdorf, S., Bugge, T.H., Behrendt, N. and Engelholm, L.H.
The non-phagocytic route of collagen uptake: A distinct degradation pathway.
J. Biol. Chem. (2011), 286: 26996-27010. [E-pub 2011, Jun 7].
Jürgensen, H.J., Madsen, D.H., Ingvarsen, S., Melander, M.C., Gårdsvoll, H., Patthy, L., Engelholm, L.H. and Behrendt N.
A novel functional role of collagen glycosylation: Interaction with the endocytic receptor uPARAP/Endo180.
J. Biol. Chem. (2011), 286: 32736-32748. [Epub 2011, Jul 18].
Gårdsvoll, H., Jacobsen, B., Kriegbaum, M.C., Behrendt, N., Engelholm, L.H., Østergaard, S. and Ploug, M.
Conformational regulation of urokinase receptor (uPAR) function. Impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction.
J. Biol. Chem. (2011), 286: 33544-33556. [Epub 2011, Jul 28].
Madsen, D.H., Jürgensen, H.J., Ingvarsen, S., Melander, M.C., Vainer, B., Egerod, K.L., Hald, A., Rønø, B., Madsen, C.A., Bugge, T.H., Engelholm, L.H. and Behrendt, N.
Endocytic collagen degradation: A novel mechanism involved in the protection against liver fibrosis.
J. Pathol. (2012), 227: 94-105. [Epub 2012, Feb 17].
Ingvarsen, S., Porse, A., Erpicum, C., Maertens, L., Jürgensen, H.J., Madsen, D.H., Melander, M.C., Gårdsvoll, H., Høyer-Hansen, G., Noel, A., Holmbeck, K., Engelholm, L.H. and Behrendt, N.
Targeting a single function of the multifunctional matrix metalloprotease MT1-MMP. Impact on lymphangiogenesis.
J. Biol. Chem. (2013), [Epub ahead of print, 2013, Feb 14].
The Behrendt Group is located at the Finsen Laboratory, a cancer research department at the Finsen Centre at Rigshospitalet, Copenhagen University Hospital.