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

癌症是世界范围内的主要死亡原因，其发病率正在上升。因此，为了发明有效的治疗方法，了解癌症发生和发展的分子机制具有全球性和紧迫的意义。程序性细胞死亡（称为凋亡）的失调是癌细胞确保自身存活的关键策略。然而，癌细胞如何逃避细胞死亡却知之甚少。肿瘤周围的基质细胞显著影响肿瘤的进展。在这里，我确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是一种神经元导向分子，已成为癌症中重要的细胞存活因子，通过其依赖性受体发挥作用。在不存在Netrin-1的情况下，这些受体诱导细胞凋亡。因此，靶向Netrin-1受体信号传导代表了一种有前途的治疗方法。我的初步数据解码了癌细胞调节Netrin-1受体诱导的细胞命运的新机制。在这里，ADAM金属蛋白酶通过脱落netrin-1受体确保细胞存活和细胞死亡之间的平衡。基于我的数据，我假设Netrin-1的消除与Netrin-1受体脱落的阻断一起诱导癌细胞凋亡。为了将我的发现转化为临床，我将开发阻断肽和/或抗体，通过引起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受体在癌细胞存活期间通过金属蛋白酶脱落的新分子机制，而且还将确定一种有前途的癌症治疗策略。

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.