Behrendt Group

Niels Behrendt´s research group is focused on cellular invasion and matrix degradation through extracellular and endocytic mechanisms, with particular emphasis to collagen matrices. The group and projects are part of the Cancer Invasion Project Group at the Finsen Laboratory.

The work includes multidisciplinary studies on the protein structure, cellular function and physiological role of collagen receptors and collagenolytic proteases. The proteins particularly in focus are uPARAP/Endo180 and other endocytic receptors for extracellular matrix proteins, as well as membrane type matrix metalloproteases (MT-MMPs). In addition to clarifying biological function, our work aims at developing model therapeutics against these proteins and using those in mouse cancer model systems. Furthermore, we explore the possibility to utilize endocytic processes for imaging or for killing or inactivation of cells that possess specific surface receptors.

Current projects

The function of the collagen receptor, uPARAP/Endo180 and related receptors

An early, major achievement of the group was the discovery and cloning of the collagen receptor, uPARAP/Endo180 (Behrendt, N. et al., J. Biol. Chem. (2000), 275: 1993-2002). This receptor is centrally engaged in collagen turnover (Kjøller, L. et al., Exp. Cell Res. (2004), 293: 106-116) and is active in collagen clearance in various physiological processes and in certain disorders including cancer invasion (Curino, A.C. et al., J. Cell Biol. (2005), 169: 977-985). Subsequently, work by other groups has shown that other receptors belonging to the same protein family may likewise be engaged in collagen turnover.

In our current projects, we clarify several aspects of the structure, function and physiological role of this family of receptors. At the molecular level, we study the structural background for their recognition of various forms and types of collagen. At the cellular level in vitro, we focus on the interplay between these receptors and collagenolytic proteases in collagen breakdown. At the physiological level, we utilize knock-out mice to study the consequences of these turnover processes in development, growth, normal physiology and cancer invasion.




Therapeutic strategies for interfering with collagen turnover in vivo, with particular emphasis to blocking monoclonal antibodies

A major strategy of the Cancer Invasion Project Group is the use of mouse monoclonal antibodies against specific mouse proteins as model therapeutics. To obtain these reagents, we utilize knock-out mice that lack critical matrix degrading components as host animals for immunization. When these mice are injected with the lacking protein, this protein will be recognized as a foreign component by the immune system, thus allowing the development of mouse monoclonal antibodies against genuine mouse proteins. Along this line, we generate large panels of antibodies against each target to allow the identification of specific “blocking” antibodies. Due to their mouse origin, these antibodies can subsequently be used for long-term studies in wildtype mice in vivo, as opposed to antibodies raised in a foreign species that would give rise to an anti-IgG response (Lund, I.K. et al., J. Biol. Chem. (2008), 283: 32506-32515).

In Niels Behrendt´s group, function blocking antibodies against mouse uPARAP/Endo180 have already been generated and antibodies against the collagenolytic protease, MT1-MMP, are currently being developed along the same line.

In close collaboration with Lars H. Engelholm´s group at the laboratory, these antibodies are being tested in mouse cancer models.




Modified matrices and tumor microenvironment

In this collaborative project with Lars H. Engelholm´s group, we exploit the fact that cells from mice with specific deficiencies with respect to collagen receptors or collagenolytic proteases display specific defects in their matrix turnover reactions (Madsen, D.H. et al., J. Biol. Chem. (2007), 282: 27037-27045). Therefore, these cells allow detailed studies on the cellular response to modified matrices in vitro whereas, in turn, the actual knock-out mice allow studies on specific changes of the matrix microenvironment in vivo. To study these responses, we isolate RNA from cultured cells and well defined tissues to obtain strictly parallel samples from wildtype mice and mice with specific deficiencies that just differ with respect to well defined matrix remodeling conditions. These samples are analyzed with respect to global gene expression patterns.




Endocytic routes for drug delivery and tumor imaging

The work on chacterizing uPARAP/Endo180 has led to a unique set of reagents and methods for manipulating with the function of this receptor. Some of these have obvious potential for various means of targeting uPARAP/Endo180-positive cells. In recently initiated, collaborative studies with Lars H. Engelholms group and several external collaborators, we exploit these possibilities. Particularly, the efficient recycling of this receptor, as well as its ability to internalize antibodies against it, offer a strong targeting potential. In these projects, we use high-affinity specific antibodies, generated in-house, as carriers for drugs or gene expression modifiers to specifically target uPARAP/Endo180-expressing cells, ultimately aiming at uPARAP/Endo180-positive tumors. In addition, we explore the possibility to use this receptor as a target component for non-invasive imaging.

Group members with personal projects

Signe Ingvarsen, MSc., PhD student
Signe Ingvarsen´s project is focused on the characterization and blocking of the membrane-type matrix metalloproteases, MT1-MMP and MT2-MMP, using monoclonal antibodies raised in knock-out mice. Signe Ingvarsen´s work is sponsored by a personal PhD stipend from the University of Copenhagen, the Faculty of Science.

Daniel H. Madsen, MSc., PhD student
Daniel Madsen is engaged in physiological studies on the collagen receptor, uPARAP/Endo180, using uPARAP/Endo180 knockout mice subjected to Various challenges, as well as double-deficient mice that lack both uPARAP/Endo180 and critical collagenolytic proteases. Daniel Madsen´s work is sponsored by a personal PhD stipend from the Hospital´s Research Council at Rigshospitalet.

Henrik J. Jürgensen, M.Sc., PhD student
Henrik Jessen Jürgensen´s project is focused on the structure/function relationship of uPARAP/Endo180 and on additional collagen receptors within the mannose receptor protein family . The work is sponsored by a personal grant from the Hospital´s Research Council at Rigshospitalet.

Maria C. Melander, PhD., Postdoc
Maria Melander works on mouse cancer models and has particular focus on the blocking of collagenolytic components, including uPARAP/Endo180, in vivo with monoclonal antibodies. The work is sponsored by a grant from the Danish National Research Foundation.