Renal Cell Carcinoma (RCC): NEDD9, Aurora kinase A (AURKA), and their interrelation with von Hippel-Lindau gene (VHL) in tumor pathology

肾癌是女性和男性最常见的10种癌症之一，其中肾细胞癌(RCC)占80%以上。透明细胞肾细胞癌(Clear cell RCC，ccRCC)是肾细胞癌最常见的亚型(75%)，与von Hippel-Lindau(VHL)基因的遗传损伤密切相关，导致HIF1和2-α表达上调，这是肾癌发病机制中的主要角色。最近发现，原癌基因AURKA和NEDD9(又称细丝形成增强子1或CAS-L)在肾癌细胞VHL缺失后被HIF-α上调，促进细胞迁移、侵袭和纤毛分解。此外，在临床前肾癌研究中，AURKA与VHL相互作用并使其磷酸化，导致肿瘤进展。我们的初步数据显示，NEDD9也与VHL相关，并且NEDD9在肾癌组织中的过度表达与患者的生存显著相关。为了测试NEDD9和AURKA是否推动RCC的进展及其参与的机制，我们将首先表征NEDD9和VHL之间的相互作用。然后，我们将使用两种不同的转基因小鼠模型和两种不同的利用人RCC细胞的模型：异种移植模型和模拟RCC肿瘤微环境的3D体外模型。这些模型将使我们能够直接测试NEDD9及其信号伙伴AURKA在肿瘤进展中的作用，以及在VHL缺乏和不存在VHL缺陷的情况下与肾癌发病相关的细胞过程中的作用。这项工作的最终目标是更好地了解肾癌发生和发展的机制，从而基于NEDD9、AURKA和VHL在肾癌中的相互作用开发新的、量身定制的治疗策略。

Kidney cancer is one of the top 10 most common cancers for both woman and men, with renal cell carcinoma (RCC) responsible for over 80% of the cases. Clear cell RCC (ccRCC) represents the most common subgroup of RCC (75% of cases) and is strongly associated with genetic lesions in the von Hippel-Lindau (VHL) gene, leading to upregulation of HIF1- and 2-alpha, major players in the pathogenesis of RCC. Recently, the oncogenes AURKA and NEDD9 (also: enhancer of filamentation 1 (HEF1) or CAS-L) were found to be upregulated by HIF-alpha upon loss of VHL in RCC cells, promoting cell migration, invasion and cilia disassembly. Moreover AURKA is interacting with and phosphorylating VHL, leading to tumor progression in preclinical RCC studies. Our preliminary data show that also NEDD9 associates with VHL and that NEDD9 overexpression in RCC samples significantly associates with patient survival.To test whether NEDD9 and AURKA drive RCC progression and which mechanisms are involved, we will first characterize the interaction between NEDD9 and VHL. Then we will employ two different transgenic mouse models and two different models utilizing human RCC cells: a xenograft model and a RCC tumor microenvironment-mimicking 3D in vitro model. These models will allow us to directly test the role of NEDD9 and its signaling partner AURKA in tumor progression and in cellular processes relevant for RCC pathogenesis in conditions with and without VHL deficiency.The ultimate goal in this work is to better understand the pathogenesis of RCC tumor initiation and progression allowing the development of novel, tailored treatment strategies based on the interplay of NEDD9, AURKA and VHL in RCC.