Through the use of techniques including two-photon microscopy, flow cytometry based cell sorting, next-generation RNA sequencing, cell biology assays, and transgenic mice we have examined the role of tumor-associated macrophages for cancer growth and for the cancer-associated extracellular matrix (ECM) degradation.
In brief, we have shown the following:
- M2-polarized macrophages are essential collagen degrading cells during tumor progression.
- The endocytic collagen receptor mannose receptor (MR) is essential for collagen degradation.
- Collagen-degrading macrophages are similar across several different types of solid cancers including breast carcinoma, lung carcinoma, melanoma and sarcoma.
- The ECM degrading M2 macrophages in tumors also express some markers of dendritic cells
- Based on next-generation RNA-sequencing and quantitative RT-PCR, the collagen-degrading M2 macrophages express enzymes that make them capable of also degrading other extracellular matrix proteins than collagen.
- The M2 macrophages do not contribute to the production of ECM as recently reported by another group.
- The ECM degrading M2 macrophages in tumors are derived from circulating inflammatory CCR2+ monocytes
- Mutual interactions between macrophages and cancer cells can contribute to the pro-tumorigenic role of tumor-associated macrophages
The research results have been presented orally at the Biennial Meeting of the American Society for Matrix Biology, St. Petersburg, FL, USA, November 13-16 and at internal seminars at the Finsen Laboratory/BRIC, University of Copenhagen.
A research paper describing the findings is currently under revision for publication in Cell Reports.
In addition to the research paper currently under revision, collaborative efforts have led to the following publications during the project period:
Kuczek, D.E. Hübbe, M.L. Madsen, D.H. Internalization of collagen: an important matrix turnover pathway in cancer. Book Chapter for ”Extracellular matrix in tumor biology”. Springer Press. In press.
Friis, S., Madsen, D.H. Bugge, T.H. (2016). Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin. J. Biol. Chem. 291(6), 2577-82.
Fan, M-H., Zhu, Q., Li1, H-H., Ra, H-J., Majumdar, S., Gulick, D.L. Jerome, J.A. Madsen, D.H. Christofidou-Solomidou, M., Speicher, D.W. Bachovchin, W.W. Feghali-Bostwick, C., Puré, E. (2016). Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lung in Mice. J. Biol. Chem. 291(15), 8070-89.
*Motley, M.P. *Madsen, D.H. Jürgensen, H.J. Spencer, D.E. Szabo, R., Holmbeck, K., Flick, M.J. Lawrence, D.A. Castellino, F.J. Weigert, R., Bugge, T.H. (2016). A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood. 127(9), 1085-96.
*equal contribution
*Engelholm, L.H. *Melander, M.C. Hald, A., Perrson, M., Madsen, D.H. Jurgensen, H.J. Johansson, K., Nielsen, C., Nøregaard, K.S. Ingvarsen, S.Z. Kjær, A., Troivik, C.S. Lærum, O.D. Bugge, T.H. Eide, J., Behrendt, N. (2016). Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180. J. Pathol. 238(1), 120-33.
Some of the findings that were not included in this research paper form the basis of other ongoing projects. In collaboration with my supervisor Niels Behrendt I will continue these projects in my new position as Junior Group Leader at the Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev.
