Abstract: Wnt signaling is well established to control endothelial cell (EC) function, but the mechanisms of vascular Wnt signaling and the contribution of vascular Wnt signaling to health and disease are still poorly understood. We have shown that autocrine-acting non-canonical Wnt signaling in EC stabilizes blood vessels and prevents vascular pruning during angiogenesis (Korn et al., Development, 2014). Moreover, we have established EC as primary source of the Wnt signaling enhancer RSPO3 (Kazanskaya et al., Development, 2008; Scholz et al., Dev Cell, 2016)). RSPO3 controls cell autonomous EC signaling during vascular maturation, but is also secreted as paracrine-acting (angiocrine) growth factor on the surrounding microenvironment. For example, central vein-derived RSPO3 has recently been shown to control liver architecture in an angiocrine manner by generating Wnt signaling gradients that regulate liver zonation (Wang et al., Nature, 2015; Rocha et al., Cell Rep. 2015). Based on the identification of cell autonomous non-canonical Wnt signaling in controlling vessel maturation and the discovery of EC-derived RSPO3 as angiocrine factor, we propose to study the role of autocrine and angiocrine Wnt signaling in tumor progression and metastasis. Employing floxed mice of the pan-Wnt secretion factor Evi/Wls and the Wnt signaling enhancer RSPO3, we will perform temporally controlled conditional vascular mutagenesis experiments to pursue a series of primary tumor and metastasis experiments using advanced mouse tumor models established in the laboratory. These include experiments with genetically-engineered mouse models (GEMM) of liver and melanoma tumorigenesis proprietarily re-derived as GEMM-derived syngraft (GDS) models as well as advanced proprietary grafted and GEMM-based surgical metastasis models. The resulting phenotypes will be analyzed focusing on the mechanisms of autocrine EC Wnt signaling contribution to tumor vascularization and metastasis as well as the consequences of angiocrine Wnt signaling for tumor progression and metastasis. The experiments will through a unique combination of established genetic Wnt signaling tools and advanced primary tumor and metastasis models shed fundamental insights into the role of vascular Wnt signaling towards tumor progression and metastasis.
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