The spontaneous development of cutaneous melanomas in Tyr-Ras+ transgenic mice on INK4a +1- and INK4a-/- backgrounds established a causal role of activated RAS in the pathogenesis of melanoma. The requirement for continuous RAS activation to maintain the viability of established tumors in the inducible Tyr/Tet-Ras+ INK4a-/-system demonstrated a critical and essential role for activated RAS in maintenance of melanomas. However, this RAS-INK4a melanoma model fails to recapitulate an important hallmark of the human disease - metastasis. It is this 'deficiency' that renders the RAS-INK4a model uniquely suitable for the discovery, characterization and validation of metastasis pathways. In this proposal, we will generate of a novel melanoma model in which the candidate progression gene, Met, can be regulated somatically in established RAS-induced non-metastatic melanomas. The impact of MET activation (and deactivation) will be examined on phenotypic, molecular/genetic and genomic levels to validate a role for MET in progression, and ultimately to delineate genes and pathways critically important for tumor progression, and possibly metastasis
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