The cysteine protease cathepsin S mediates niche activation through effects of the tumor cells and stroma cells of the micronevironment in brain metastases: approaches

半胱氨酸蛋白酶组织蛋白酶 S 通过脑转移中微环境的肿瘤细胞和基质细胞的作用介导生态位激活：方法

• 批准号: 216995176
• 负责人: Professorin Dr. Lisa Sevenich, Ph.D.
• 金额: --
• 依托单位: Department of Fundamental Oncology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/216995176?language=en
• 关键词: cysteine; protease; cathepsin; mediates; niche

Metastasis remains the single most lethal aspect of cancer. Despite advances in the treatment of local cancers, few therapies succeed at combating disseminated disease, particularly for brain metastases. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Therefore I aim to analyze tumor-stroma interactions in brain metastasis to potentially identify novel therapeutic targets. Preliminary data suggest that the cysteine protease cathepsin S (CatS) is a key mediator of experimentally induced brain metastasis in a xenograft mouse model. CatS shows a particularly intriguing expression pattern, with high expression in tumor cells early in metastatic development, which is downregulated at the later stages concomitant with an increase in stromal CatS expression. Interestingly, only the combined depletion of both tumor and stromal derived CatS significantly reduced brain metastasis incidence. Thus, the aim of my project is to identify mechanisms by which CatS regulates distinct steps of brain colonization. In addition to the model I used for the preliminary experiments, I seek to establish other brain metastasis mouse models to verify the generalizability of my findings. Moreover, I will test the efficacy of a pharmacological inhibition of CatS on brain metastasis in pre-clinical trials. In order to determine a possible correlation with patient prognosis, I will analyze the cell-type specific expression of CatS in pathology samples. I strongly believe that the findings on the role of CatS in brain metastasis will be beneficial for understanding tumor-stroma interaction and provide a strong scientific foundation for the future development of novel, effective therapeutic strategies for this devastating disease.

转移仍然是癌症最致命的一个方面。尽管局部癌症的治疗取得了进展，但很少有疗法能够成功对抗播散性疾病，尤其是脑转移瘤。虽然肿瘤微环境已成为其他器官部位癌症进展的主要调节因素，但目前我们对脑转移微环境的了解非常有限。因此，我的目标是分析脑转移中肿瘤与基质的相互作用，以潜在地识别新的治疗靶点。初步数据表明，半胱氨酸蛋白酶组织蛋白酶 S (CatS) 是异种移植小鼠模型中实验诱导脑转移的关键介质。 CatS 显示出一种特别有趣的表达模式，在转移发展早期的肿瘤细胞中高表达，在后期随着基质 CatS 表达的增加而下调。有趣的是，只有肿瘤和基质来源的 CatS 联合消除才能显着降低脑转移发生率。因此，我的项目的目的是确定 CatS 调节大脑定植的不同步骤的机制。除了我用于初步实验的模型外，我还寻求建立其他脑转移小鼠模型来验证我的研究结果的普遍性。此外，我将在临床前试验中测试 CatS 的药理抑制对脑转移的功效。为了确定与患者预后可能存在的相关性，我将分析病理样本中 CatS 的细胞类型特异性表达。我坚信，CatS 在脑转移中的作用的发现将有助于理解肿瘤-基质相互作用，并为未来开发针对这种破坏性疾病的新颖、有效的治疗策略提供坚实的科学基础。