Project 9

1. Applicant

2. Topic

Role of developmentally relevant signaling pathways and transcription programs in the pathogenesis of UV-induced primary and metastatic melanomas in a new genetic mouse model

3. Short summary

Epidemiological studies have shown that UV radiation – particularly during childhood - is the most important environmental factor associated with the incidence of melanoma in the caucasian population. We have recently established the HGFxCDK4R24C mouse melanoma model in our laboratory. HGFxCDK4R24C mice develop primary cutaneous and metastasizing melanomas following neonatal UV irradiation. Using this novel UV-responsive genetic mouse melanoma model, we will experimentally investigate the cellular and molecular mechanisms of UV-induced melanomagenesis. Based on preliminary evidence we hypothesize that progressive growth of UV-induced melanomas involves deregulation of signaling pathways and transcription programs which normally control the maintenance of the melanocyte stem cell niche and the appropriate proliferation, survival, migration and positioning of melanocytes in the skin. In this research project we propose (a) to characterize the expression of developmentally relevant signaling molecules and transcription factors active in UV-induced primary and metastatic melanomas and (b) to show the functional relevance of these molecules for melanoma growth and progression in primary cell culture and tumor transplantation assays. In our studies, we hope to identify novel aspects of UV-induced genetic and epigenetic changes which contribute to melanoma development and may eventually serve as targets for therapeutic intervention.

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