Decoding the role of Netrin-1 receptor shedding during cancer cell survival

癌症是世界范围内主要的死亡原因，其发病率还在上升。因此，为了发明有效的治疗方法，了解肿瘤发生发展的分子机制具有全球性和迫切性。解除对程序性细胞死亡的调控，即所谓的凋亡，是癌细胞确保自身生存的关键策略。然而，人们对癌细胞如何逃脱细胞死亡知之甚少。间质细胞周围的肿瘤显著影响肿瘤的进展。在这里，我鉴定了分泌的细胞外基质蛋白Netrin-1在基质细胞中高度上调，以响应侵袭性癌细胞的刺激。Netrin-1是一种神经导向分子，通过其依赖受体发挥作用，已成为癌症中必不可少的细胞生存因子。在没有Netrin-1的情况下，这些受体诱导细胞凋亡。因此，靶向Netrin-1受体信号通路是一种很有前途的治疗方法。我的初步数据破译了一种癌细胞调节Netrin-1受体诱导细胞命运的新机制。在这里，ADAM金属蛋白水解酶通过释放Netrin-1受体来确保细胞存活和细胞死亡之间的平衡。根据我的数据，我假设Netrin-1的消除和Netrin-1受体脱落的阻断共同诱导了癌细胞的凋亡。为了将我的发现转化为临床，我将开发封闭肽和/或抗体，通过导致癌细胞死亡来抑制肿瘤进展。因此，该项目的成功完成不仅将深入了解Netrin-1受体在癌细胞存活过程中通过金属蛋白酶脱落的新的分子机制，而且还将确定一种有前景的癌症治疗策略。

Cancer is a leading cause of death worldwide and its incidence is rising. Therefore, in order to invent effective therapeutics, it is of global and urgent interest to understand the molecular mechanisms of cancer development and progression. Deregulation of programmed cell death, known as apoptosis, is a key strategy of cancer cells to ensure their own survival. However, how cancer cells escape cell death is poorly understood. Tumour surrounding stromal cells significantly influence tumour progression. Here, I identified the secreted extracellular matrix protein Netrin-1 to be highly up-regulated in stromal cells in response to invasive cancer cell stimuli. Netrin-1, a neuronal guidance molecule, has emerged as an essential cell survival factor in cancer, acting through its dependence receptors. In the absence of Netrin-1, these receptors induce apoptosis. Thus, targeting Netrin-1 receptor signalling represents a promising therapeutic approach. My preliminary data decode a novel mechanism through which cancer cells regulate Netrin-1 receptor induced cell fate. Here, ADAM metalloproteases ensure the equilibrium between cell survival and cell death by shedding netrin-1 receptors. Based on my data, I hypothesize that elimination of Netrin-1 together with blockade of Netrin-1 receptor shedding induces cancer cell apoptosis. To translate my findings into the clinic, I will develop blocking peptides and/or antibodies to inhibit tumour progression by causing cancer cell death. Thus, successful completion of this project will not only yield in-depth insight into a novel molecular mechanism of Netrin-1 receptor shedding through metalloproteases during cancer cell survival, but also identify a promising strategy for cancer therapy.