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

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，但很少有疗法能成功地对抗播散性疾病，特别是脑转移。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子，但我们对脑转移微环境的了解目前非常有限。因此，我的目标是分析脑转移瘤中肿瘤-间质的相互作用，以潜在地确定新的治疗靶点。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的脑转移的关键介质。CatS显示出特别有趣的表达模式，在转移发展的早期在肿瘤细胞中具有高表达，其在后期阶段下调，伴随着基质CatS表达的增加。有趣的是，只有肿瘤和基质来源的CatS两者的联合消耗显著降低脑转移发生率。因此，我的项目的目的是确定CatS调节大脑殖民的不同步骤的机制。除了我用于初步实验的模型外，我试图建立其他脑转移小鼠模型来验证我的发现的普遍性。此外，我将在临床前试验中测试CatS对脑转移的药理学抑制的功效。为了确定与患者预后的可能相关性，我将分析病理样本中CatS的细胞类型特异性表达。我坚信，关于CatS在脑转移中作用的研究结果将有助于理解肿瘤-间质相互作用，并为未来开发这种毁灭性疾病的新型有效治疗策略提供坚实的科学基础。

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.