Investigation of molecular mechanisms of TIMP-1-induced metastasis via shRNA technology

• Applicant: Professor Dr. Achim Krüger
• Subject Area: Hematology, Oncology
• Term: from 2006 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 24756627

Tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural broad spectrum inhibitor of metalloproteinases, is associated with poor prognosis and short survival of cancer patients. In the previous two funding periods we could show that elevated systemic TIMP-1 levels not only increase the tumor cell-intrinsic metastatic potential, but also induce the formation of a pre-metastatic niche in the liver, where neutrophil granulocytes (NGs) act as functional mediators of increased liver metastasis. Our un-published data indicate that TIMP-1 affects NG homeostasis not only in the liver, but also leads to increased NG counts in peripheral blood. This is interesting as high blood NGs are described to promote particularly liver metastasis. Furthermore, NGs can contribute to a pro-metastatic local microenvironment by secreting cytokines or proteases.In the last funding period we would therefore like to clarify whether the increase of NG numbers in the blood contributes to TIMP-1-induced liver metastasis, and at what level TIMP-1 impacts on NG homeostasis in the blood as well as in the liver. The main questions are:1. What is the mechanism of TIMP-1-induced increase of blood NGs?2. What are the pro-metastatic effects of NGs in the TIMP-1-induced pre-metastatic niche in the liver?3. Does interaction of tumor cells with NGs in the blood contribute to TIMP-1-induced liver metastasis?From the results we expect a deeper understanding of the interplay of local tissue homeostasis, the immune compartment, and tumor cells. This will explain clinical observations concerning TIMP-1 in the context of inflammation and cancer progression.

• DFG Programme: Research Grants