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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MatrixMacrophages (Matrix degrading macrophages in cancer growth and invasion)

Teaser

Summary

Macrophages that infiltrate tumors are believed to support tumor growth and facilitate metastasis but the underlying mechanisms are incompletely understood. Cancer progression and metastasis involve degradation of the surrounding extracellular matrix. In this project we have examined the role of tumor-associated macrophages for this process and investigated their effect on cancer progression in mouse models of cancer.

The outcome of the project provides important new information about the biology of tumors and it indicates that targeting of tumor-associated macrophages could form the basis of a novel type of cancer therapy.

The project consists of two major objectives:
1) To examine the role of tumor-associated macrophages for extracellular matrix degradation
2) To examine the role of tumor-associated macrophages for cancer progression

Work performed

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., HuÌˆbbe, M.L., Madsen, D.H. Internalization of collagen: an important matrix turnover pathway in cancer. Book Chapter for â€Extracellular matrix in tumor biologyâ€. 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., PurÃ©, 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., JÃ¼rgensen, 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., NÃ¸regaard, K.S., Ingvarsen, S.Z., KjÃ¦r, A., Troivik, C.S., LÃ¦rum, 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.

Final results

The findings from this project provides important new information about the biology of tumors and it indicates that targeting of tumor-associated macrophages could form the basis of a novel type of cancer therapy.
The findings form the basis of future efforts towards the development of cancer therapy, which targets the tumor-associated macrophages. The potential of combining such therapy with cancer immunotherapy will be investigated in pre-clinical mouse models.