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

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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.