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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma with a 5-year survival rate of only 10.5%, and chemotherapy and radiotherapy regimen have shown limited efficacy. On the molecular level, significant inter- and intra-tumor heterogeneity hamper identification of drug targets, biomarkers and unraveling of disease mechanisms. We developed a novel patient-derived model system of ccRCC that recapitulates the heterogeneity of the originating cancer enabling us to study ccRCC on a functional level. In five rounds and in three biological replicates of an in vivo selection, we transplanted the metastases of orthotopically transplanted tumor cells into the renal capsules of NOD scid gamma (NSG) mice. The tumor was enriched for cells with higher growth and metastatic potential compared to the initial heterogeneous population. Comparative gene-expression analysis revealed candidate genes associated with enhanced malignant growth and metastasis. Absolute shrinkage and selection operator (LASSO) regression identified a gene signature that can robustly predict patient survival. The prognostic power of our signature was additionally verified in independent patient cohorts suggesting that this approach leverages efficient stratification of patients into distinctive risk groups. One of the hallmark genes in this signature is known to alter cellular signaling properties. Therefore, we hypothesized that this gene contributes to tumor growth and metastasis and thus to aggressiveness of ccRCC. In fact, in knockdown and overexpression xenografts experiments we could confirm an essential role for tumor aggressiveness in vivo suggesting that the gene and associated downstream signaling pathways are attractive targets for treatment of clear cell renal cancer. Citation Format: Felix Geist, Teresa Dolt, Thomas Höfner, Corinna Klein, Vanessa Vogel, Albrecht Stenzinger, Tim Holland-Letz, Ornella Kossi, Wilko Weichert, Peter Schirmacher, Sascha Pahernik, Markus Hohenfellner, Andreas Trumpp, Martin Sprick. A clear cell renal cancer metastasis model identifies novel mediators of tumor aggressiveness and predictors of patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1063.