The molecular and genetic events which contribute to the initiation and progression of cutaneous malignant melanoma, an aggressive disease with a high propensity for metastasis, are poorly understood. However, it is currently appreciated that receptor tyrosine kinases (RTKs) are frequent targets of oncogenic disruption during melanomagenesis.
Major aims of the Molecular Genetics Section are to establish relevant RTK- based mouse models for human melanoma, develop reagents for elucidating the specific roles of RTK signaling in melanomagenesis, and identify novel or otherwise under-appreciated genes involved in melanoma progression. In addition, where feasible, information gleaned from these studies are being applied to the generation and testing of potentially useful therapeutic agents. We have created a mouse model of metastatic melanoma in which oncogenesis was induced through forced expression of a transgenic hepatocyte growth factor/scatter factor (HGF/SF) ligand, and apparent selection of tumor cells overexpressing its endogenous receptor, Met. Data from this useful mouse model have indicated that constitutive HGF/SF-Met signaling can play a causal role in the development of melanoma and acquisition of the metastatic phenotype. We are also assessing the anti-melanoma potential of novel soluble RTK mutants that effectively block receptor function in vivo through a dominant negative mechanism. We have recently discovered that a natural splice variant of HGF/SF, NK2, antagonizes the pathological consequences of HGF/SF, and discourages the subcutaneous growth of transplanted melanoma cells. Remarkably, the metastatic efficiency of these melanoma cells is dramatically enhanced, rather than reduced, when transplanted into transgenic NK2 host mice. Considered in conjunction with reports that NK2 can induce scatter in vitro, these data strongly suggest that cellular motility is a critical determinant of metastasis. Moreover, our results show how alternatively structured ligands can be exploited in vivo to functionally dissociate Met- mediated activities and their downstream pathways. In another project, we have demonstrated that mammary tumorigenesis in a bitransgenic mouse model occurs with an enhanced mutation frequency and a shift in the spectrum of mutations, supporting the notion that breast cancer develops in association with an inherent genetic instability. - melanoma, Metastasis, mutagenesis in vivo, genetically engineered mouse models, receptor tyrosine kinase signaling, Dominant Negative Receptor, HGF/SF, Fibroblast Growth Factor, Antagonist, - Neither Human Subjects nor Human Tissues
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