Krüger, Achim

Structure-function analysis and cell-signaling of metastasis-promoting multi-functional protease inhibitors

Proteases and their natural inhibitors control virtually all processes of life by controlling and remodeling the proteins in the microenvironment of any cell, its receptors, as well as growth factors. Imbalance of proteases and protease inhibitors promotes detrimental inflammatory processes during infections, tumor growth, and cancer metastasis.
We study the non-canonical function of Tissue-inhibitors of metalloproteinases (TIMPs), namely their newly-discovered potential to act, unexpectedly, as a cell signaling-inducing cytokine, which triggers pro-inflammatory function in immune cells as well as other organ-resident cells.
We have identified the multi-functionality of TIMP-1 and could thereby explain the paradox that TIMP-1 correlates with bad prognosis of many diseases, although its canonical anti-proteolytic activity had led to the prediction that TIMP-1 should inhibit them.
We employ a wide spectrum of technologies encompassing all aspects of molecular cloning/genetic engineering, expression-vector design, biochemistry, cell culture including functional cell-assays, metabolic assays, protein-design and purification, flow-cytometry, histology, in silico-modeling, statistical analyses etc. in order to explore new structure-function relationships between TIMPs and their receptors, which we also identify in the process.
Through cooperation with colleagues in the clinic we constantly validate our data with material from the clinic towards a transfer of new knowledge from bench to the bedside.

Examples of publications from our group (PhD students in bold):
-    Hermann, C.D., B. Schoeps, C. Eckfeld, E. Munkhbaatar, L. Kniep, O. Prokopchuk, N. Wirges, K. Steiger, D. Häußler, P. Knolle, E. Poulton, R. Khokha, B.T. Grünwald, I.E. Demir, A. Krüger. TIMP1 expression underlies sex-disparity in liver metastasis and survival in pancreatic cancer. J Exp Med 218 : e20210911, 2021.           
-    Schoeps, B., C. Eckfeld, L. Flüter, S. Keppler, R. Mishra, P. Knolle, F. Bayerl, J. Böttcher, C.D. Hermann, D. Häußler, A. Krüger. Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1). J Biol Chem 297 : 101072, 2021.
-    Schoeps, B., C. Eckfeld, O. Prokopchuk, J.P. Böttcher, D. Häußler, K. Steiger, I.E. Demir, P. Knolle, O. Soehnlein, D.E. Jenne, C.D. Hermann, A. Krüger. TIMP1 triggers neutrophil extracellular trap formation in pancreatic cancer. Cancer Res 81 : 3568-3579, 2021.
-    Eckfeld, C., D. Häußler, B. Schoeps, C.D. Hermann, A. Krüger. Functional disparities within the TIMP family in cancer: hints from molecular divergence.  Cancer Metastasis Rev 38 : 469-481, 2019.
-    Grünwald, B., B. Schoeps, A. Krüger. Recognizing the molecular multifunctionality and interactome of TIMP-1. Trends Cell Biol 29 : 6-19, 2019.
-    Grünwald, B., V. Harant, S. Schaten, M. Frühschütz, R. Spallek, B. Hoechst, K. Stutzer, S. Berchtold, M. Erkan, O. Prokopchuk, M. Martignoni, I. Esposito, M. Heikenwaelder, A. Gupta, J. Siveke, P. Saftig, P.A. Knolle, D. Wohlleber, A. Krüger, Pancreatic pre-malignant lesions secrete TIMP1, which activates hepatic stellate cells via CD63 signaling to create a pre-metastatic niche in the liver. Gastroenterology 151 : 1011-1024, 2016.
-    Seubert, B., B. Grünwald, J. Kobuch, H. Cui, F. Schelter, S. Schaten, J.T. Siveke, N.H. Lim, H. Nagase, N. Simonavicius, M. Heikenwalder, T. Reinheckel, J.P. Sleeman, K.P. Janssen, P. Knolle, A. Krüger. TIMP-1 creates a pre-metastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 61 : 238-248, 2015.
-    Cui, H., B. Seubert, E. Stahl, H. Dietz, U. Reuning, L. Moreno-Leon, M. Ilie, H. Nagase, B. Mari, A. Krüger. Tissue inhibitor of metalloproteinases-1 induces a pro-tumorigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene 34 : 3640-3650, 2015.