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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Mohla, Suresh
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Dana-Farber Cancer Institute
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