Elucidating the role of the receptor tyrosine kinase Ror2 within the Wnt pathway and its contributions to renal cell carcinoma tumorigenesis

Ror2, an important mediator of Wnt signaling cascades, has been shown to be aberrantly expressed in RCC promoting cell migration, invasion, and tumor growth. In this work, our goal was to elucidate the role of Ror2 as a Wnt receptor within its contextual expression of RCC. Utilizing microarrays we examined gene expression in RCC tumors and found Ror2 was significantly correlated with expression of several Wnt signaling genes including the classical feedback target gene, Axin2. Subsequent analysis in RCC cells showed that Ror2 expression results in a poised state for canonical Wnt signaling through an increased signaling pool of beta-catenin, leading to an enhancement of target genes following Wnt3a stimulation. In addition, we utilized siRNA and dickkopf to inhibit LRP6 in order to show that Ror2 stabilization of beta-catenin was independent of LRP6 but required for the downstream response to Wnt3a. Finally, we also saw that the Ror2 kinase domain is required for stabilization of soluble beta-catenin and enhancement of canonical signaling. Due to Ror2's correlation with aggressive disease in several cancers we have aimed to examine its contributions to cell migration and tumor growth, and its potential as a prognostic biomarker for RCC. Utilizing RCC cells and human tumors we have shown that both MMP2 and SFRP2 exhibit a significant correlation with Ror2. We show that Ror2 expression results in increased cell migration that is dependent upon an intact Ror2 kinase domain. We also examined the effects of Ror2 overexpression in xenografts and found that Ror2 expression results in increased tumor growth and vascularity. To ascertain the potential of Ror2 as a prognostic biomarker we first examined Ror2 expression in relation to the ccA and ccB molecular subtypes in RCC tumors, finding that Ror2 expression was significantly higher in ccB. Finally we assessed Ror2's potential as an independent prognostic biomarker for RCC; we show that high Ror2 expression correlates with increased tumor growth and significant reduction in overall survival. These results exhibit Ror2's potential as a prognostic biomarker and therapeutic target for RCC.Doctor of Philosoph