Mutant BRAF-regulated transcription factors in melanoma progression

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? DESCRIPTION (provided by applicant): Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying disease progression in order to better predict and identify aggressive forms of melanomas. The serine/threonine kinase, BRAF, is somatically mutated in 40-60% of melanomas. BRAF mutations are early events that lead to hyper-activation of MEK-ERK1/2 signaling and melanoma growth and invasion. While BRAF inhibitors are now first-line therapies for metastasized mutant V600E BRAF melanomas, they only delay mortality and are not being administered in the adjuvant setting. Thus, we must enhance our understanding of the mechanisms underlying growth and invasion of early-stage melanomas in order to improve early diagnosis and treatment strategies that prevent metastasis. We have identified transcription factors, TWIST1 and FOXD3, which are regulated by mutant BRAF in melanoma. In this proposal, we seek to determine the role of TWIST1 and FOXD3 in invasion and dormancy during the early steps of melanoma progression. We propose three Specific Aims to determine the role of TWIST1 in invasion of primary melanoma using 3D skin mimetic and mutant BRAF mouse models, to mechanistically understand FOXD3 regulation of SOX2 (a transcription factor linked to induced pluripotency), and to examine the interplay between TWIST1, FOXD3 and SOX2 in vivo. At the completion of our experiments, we expect to have demonstrated that the interplay between mutant BRAF-regulated transcription factors controls mechanisms that underlie melanoma plasticity and steps in the metastatic cascade.
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