Impact of TIMP-1 in the host microenvironment on modification of the new prognostic marker L1CAM during liver metastasis

• Applicant: Professor Dr. Achim Krüger
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 122660502

In this project we aim for establishing a functional relationship between the cell adhesion molecule L1CAM, the natural metalloprotease inhibitor TIMP-1 and the Sheddase ADAM-10. High expression levels of L1CAM on tumor cells and high systemic levels of TIMP-1 in the host are associated with bad prognosis of cancer patients and promotion of tumor cell metastasis. ADAM-10 is a known sheddase of L1CAM and was found to be inhibited by TIMP-1. On this basis we hypothesize that elevated systemic levels of TIMP-1, which then are present also in the microenvironment of the tumor cell, contribute to increase of the metastatic potential of tumor cells by stabilizing the cell surface presence of L1CAM on the tumor cell surface by inhibiting the sheddase function of ADAM-10. First, we aim to investigate in vitro whether exposure of tumor cells to exogenous recombinant TIMP-1 induces L1CAM protein, via inhibition of ADAM-10, at the tumor cell surface. In the next step, we aim to elevate TIMP-1 levels systemically in the host and investigate, whether the previously observed promotion of experimental metastasis correlates with L1CAM expression on the tumor cells. Further, we aim to investigate whether inhibition of ADAM-10 by TIMP-1 leads to compensation by increasing the expression and functional activity of the alternative L1CAM sheddases, ADAM-17 and Plasmin, which are not inhibited by TIMP-1 and whether this compensation within the complex proteolytic network has consequences in vivo. Since metastasis seems to almost always rely on the increased activity of the HGF/Met signalling pathway and we found that this pathway mediates the metastasis-promoting effect of elevated exogenous TIMP-1 levels in the organism, we aim to elucidate a possible regulation of L1CAM on the gene expression level. The TIMP-1-induced stabilization of Met at the cell surface that we had previously found may trigger gene expression of L1CAM. Elucidation of the interplay between TIMP-1 and L1CAM during metastasis will provide important hints for the development of new therapies of malignant tumors.

• DFG Programme: Research Grants