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Mechanisms of UV-Induced Melanoma Initiation

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[Technical Report, Annual Report]

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In this Team Science Award, we seek to understand the difference between nevi that will become melanomas and those that are stable for the lifetime of a patient, and to determine exactly what role UV exposure plays in increasing the rate of melanoma. By understanding how UV causes melanoma formation, we can meet our main objectives i to identify clinically approved compounds that decrease the risk that a nevus will transform and ii to identify molecules that allow us to determine which moles are more likely to become melanoma, and which are stable. In Year 1 of this project, we found that inhibition of EPAC downstream of MC1R via a PKA independent mechanism linked to AKT signaling blocked the tumor-initiating state. Thus, our data suggest that non-canonical activation of MC1R signaling induces a melanoma initiating state and we are currently optimizing identification of appropriate markers on nevus tissues. We are currently working to develop animal models to target this pathway and to validate it in UV-treated human nevi. If we are able to demonstrate this phenomenon in animal and nevus models as proposed in Years 2 and 3, we will have a new, even paradigm-shifting, understanding of how sunlight triggers melanoma initiation and candidate strategies to prevent nevus transformation from occurring.


Subject Categories:

  • Medicine and Medical Research

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[A, Approved For Public Release]