Cellular Metabolic Responses to TIMP-1 Signaling-Induced Stress Mimicry in the Context of Liver Metastasis

• Applicant: Professor Dr. Achim Krüger
• Subject Area: Hematology, Oncology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413212193

Metastasis, the spread of tumor cells throughout the body, and cachexia, a wasting syndrome characterized by weight loss due to muscle atrophy and loss of fat mass, are the main causes of the high mortality rate in pancreatic cancer. New studies suggest that both manifestations of the disease interfers with the metabolism and therefore with the entire organism. Tumor cells have a high need for nutrients due to their rapid growth, which they often have to support under low-oxygen conditions, while cachexia is accompanied by muscle protein and fat degradation. It is unclear whether there could be a superordinate regulator for both manifestations. Our previous work showed that Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein secreted by most tumors, is found in the blood at levels correlating with progression of liver metastasis in men as well as in cachexia, changes the liver's homeostasis, and changes the metabolic programming of different cell types through its increasingly recognized cytokine and pro-inflammatory function as a receptor ligand. The aim of this research project is to systematically analyze in mouse models and in vitro whether TIMP-1 is a governing factor for the regulation of pro-cachectic cellular metabolic responses via the liver as a central organ regulating metabolism. Our preliminary data already show a signaling pathway through which TIMP-1 can reprogram the metabolism of hepatocytes. One goal in this project is to clarify, with the help of unbiased single-nucleus RNA analysis, transcriptomics, and secretomics technologies, whether TIMP-1 also reprograms other hepatic cells in such a way that the liver induces typical cachexia parameters in muscle and fat tissue via the release of to be identified secreted cytokines and metabolites. Since TIMP-1 is present systemically in the blood, another goal is to clarify whether, and via which of the TIMP-1 receptors and signaling pathways, muscle and fat cells are reprogrammed by TIMP-1 directly. To this end, our preliminary data show that TIMP-1 significantly lowers lipid content in fat cells and induces atrophy markers in muscle cells in an TIMP-1-dependent manner. In summary, by identifying the central role of TIMP-1, we expect completely new insights into the mechanisms of cachexia formation in pancreatic cancer, which would support better diagnostics and strategies for more effective systemic therapies. Since TIMP-1 is increased in almost all types of cancer, we expect a broad relevance of our study. Additionally, our previous publication on the male-specific increase of TIMP-1 levels in pancreatic cancer, and work by others indicating that cachexia occurs more frequently in male patients, results in an additional, highly timely advancement by taking biological sex into account in personalized diagnostics and therapy.

• DFG Programme: Research Grants