Identification of a Novel Wnt Inhibitor

Cancer cells are embedded in a microenvironment composed of stromal cells, such as fibroblasts, endothelial cells, infiltrating immune cells, as well as non-cellular compartments such as the extracellular matrix and secreted soluble factors. For successful tumorigenesis and metastasis to occur, it has been shown that cancer cells cannot rely exclusively on cellautonomous properties; instead, the cells also require a permissive microenvironment. This suitable microenvironment is formed as a result of the communication of cancer cells with stromal cells through either direct or indirect communication. The release of soluble factors such as chemokines is a major mechanism for cell-cell communication within the tumor microenvironment and contributes to the generation of supportive metastatic niches. Apart from its known function in leukocyte recruitment, recently chemokines and their receptors have emerged as crucial factors in all stages of tumor development, such as angiogenesis and directing of tumor cells to preferential metastatic sites. We had previous evidence that Wnt signals are important for the establishment of lung metastasis of breast cancer cells. In order to extend this observation to additional tumor models, this thesis aimed to test the role of Wnt signaling in the process of melanoma metastasis. A mouse model using B16F10 mouse melanoma cell line was developed to contain a Wnt reporter. These cells were responsive to Wnt stimulation in vitro and pulmonary metastasis assay showed that Wnt signalling is active in these cells, establishing Wnt signalling activity as a property of melanoma metastasis. Previous work in our laboratory has identified a chemokine as an inhibitor of the Wnt signaling pathway. In this thesis, it is shown through in vitro analysis that the inhibition of Wnt signaling is likely to be at the membrane level, possibly by interfering with LRP6 function. In vivo, expression of this chemokine in B16F10 melanoma cells strongly abolishes lung metastasis. This inhibition is not dependent on the chemotactic function of this chemokine, as the repression of lung metastasis persists in the absence of T, B, and NK cells or the expression of mutants of this chemokine that have impaired chemotactic activity and/or its receptor binding. Further to establishing the Wnt pathway as an important component in melanoma metastatic colonization, this thesis aim to develop novel therapeutics which could interfere with Wnt signaling and may be useful in the future to treat metastatic disease.