Daniel H. Madsen

Ph.d. student

Key Research Interests
My research focuses on understanding the interplay between extra- and intracellular collagen degradation and the role of these processes in conditions such as cancer invasion.

Current project
The degradation of the extracellular matrix component collagen is engaged in both physiological and pathological processes such as bone development and cancer growth and invasion. Most research concerning collagen degradation has focused on the extracellular degradation of collagen carried out by certain proteases named matrix metalloproteases (MMPs). My research focuses on a recently discovered route of collagen turnover that involves intracellular collagen degradation and is governed by the collagen receptor, urokinase plasminogen activator receptor-associated protein (uPARAP). uPARAP directs the internalization and subsequent lysosomal degradation of collagen and this pathway of collagen degradation has been shown to have importance both in vitro and in vivo. Importantly, in a mouse model of breast cancer uPARAP deficiency leads to a reduced tumor growth accompanied by large collagen accumulations. My research has primarily focused on studying the interplay between the intracellular collagen degradation pathway mediated by uPARAP and the extracellular MMP-mediated pathway of collagen degradation. Biochemical and cell biology studies on this aspect have led to indications that uPARAP and MMPs function in a cooperative manner in the overall process of collagen degradation.
Future studies will focus on elucidating whether these cell culture observations can be extended to in vivo situations. This will include the examination of mice that are deficient of both uPARAP and various other components required for collagen degradation.
Little is known about the molecular mechanism of uPARAP regarding ligand binding and endosomal release and additional work will include biochemical and protein chemical studies to learn more about these molecular aspects of uPARAP.
Madsen DH, Engelholm LH, Ingvarsen S, Hillig T, Wagenaar-Miller RA, Kjøller L, Gårdsvoll H, Høyer-Hansen G, Holmbeck K, Bugge TH, 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 Sep 14;282(37):27037-45.

Sulek J, Wagenaar-Miller RA, Shireman J, Molinolo A, Madsen DH, Engelholm LH, Behrendt N, Bugge TH.
Increased expression of the collagen internalization receptor uPARAP/Endo180 in the stroma of head and neck cancer.
J Histochem Cytochem. 2007 Apr;55(4):347-53.

Career
2004: 6-months research project at the University of Barcelona.

2007: Masters degree in Biochemistry, the University of Copenhagen.

2007: 6-months stay in the research group of Thomas H. Bugge, NIDCR, National Institutes of Health, Bethesda, USA.