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

转移（肿瘤细胞在全身的扩散）和恶病质（一种因肌肉萎缩和脂肪量减少而导致体重减轻的消瘦综合征）是胰腺癌高死亡率的主要原因。新的研究表明，这种疾病的两种表现都干扰了新陈代谢，从而干扰了整个生物体。肿瘤细胞由于生长迅速，对营养物质的需求量很大，往往需要在低氧条件下维持营养，而恶病质则伴随着肌肉蛋白和脂肪的降解。目前尚不清楚是否会有一个针对这两种表现的上级监管机构。我们之前的研究表明，组织金属蛋白酶1 （TIMP-1）是一种由大多数肿瘤分泌的蛋白，在男性肝脏转移和恶病质的血液中发现，其水平与肝脏转移的进展相关，通过其作为受体配体的细胞因子和促炎功能，改变肝脏的稳态，改变不同细胞类型的代谢程序。本研究项目的目的是在小鼠模型和体外系统分析TIMP-1是否是通过肝脏作为调节代谢的中心器官调节前病毒质细胞代谢反应的调控因子。我们的初步数据已经显示TIMP-1可以通过信号通路重新编程肝细胞的代谢。该项目的一个目标是在无偏单核RNA分析、转录组学和分泌组学技术的帮助下，澄清TIMP-1是否也以这样一种方式重编程其他肝细胞，即肝脏通过释放待识别的分泌细胞因子和代谢物在肌肉和脂肪组织中诱导典型的恶病质参数。由于TIMP-1在血液中系统性存在，另一个目标是澄清TIMP-1受体和信号通路中，肌肉和脂肪细胞是否直接被TIMP-1重编程，以及通过哪一种。为此，我们的初步数据表明，TIMP-1显著降低脂肪细胞中的脂质含量，并以TIMP-1依赖的方式诱导肌肉细胞中的萎缩标志物。总之，通过确定TIMP-1的核心作用，我们期望对胰腺癌恶病质形成机制有全新的认识，这将支持更好的诊断和更有效的全身治疗策略。由于TIMP-1在几乎所有类型的癌症中都增加，我们期望我们的研究具有广泛的相关性。此外，我们之前发表的关于胰腺癌中男性特异性TIMP-1水平升高的文章，以及其他人的研究表明恶病质在男性患者中更频繁地发生，通过在个性化诊断和治疗中考虑生理性别，导致了额外的、高度及时的进展。

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.