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，以及恶病质，一种以由于肌肉萎缩和脂肪量减少导致的体重减轻为特征的消耗综合征，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会干扰新陈代谢，从而影响整个生物体。肿瘤细胞由于其快速生长而对营养物质有很高的需求，它们通常必须在低氧条件下支持，而恶病质伴随着肌肉蛋白质和脂肪降解。目前还不清楚是否有一个上级监管机构对这两种表现。我们以前的工作表明，金属蛋白酶组织抑制剂-1（TIMP-1）是一种由大多数肿瘤分泌的蛋白质，在血液中以与男性肝转移进展以及恶病质相关的水平存在，改变肝脏的稳态，并通过其日益认可的细胞因子和促炎功能作为受体配体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地分析TIMP-1是否是通过肝脏作为调节代谢的中枢器官来调节恶病质前细胞代谢反应的主导因素。我们的初步数据已经显示了TIMP-1可以重新编程肝细胞代谢的信号通路。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是否也以这样的方式重编程其他肝细胞，即肝脏通过释放待鉴定的分泌细胞因子和代谢物诱导肌肉和脂肪组织中的典型恶病质参数。由于TIMP-1是全身性存在于血液中，另一个目标是澄清是否，并通过哪些TIMP-1受体和信号通路，肌肉和脂肪细胞被TIMP-1直接重编程。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依赖性方式诱导肌细胞中的萎缩标志物。总之，通过确定TIMP-1的核心作用，我们期待对胰腺癌恶病质形成机制的全新见解，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TIMP-1水平男性特异性增加的文章，以及其他人的工作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物性别，导致了额外的高度及时的进步。

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.