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Malignant melanoma is the deadliest form of skin cancer and is poorly treatable. Depth of melanoma invasion into the dermis is used as a clinical determinant of a poor prognosis. Our long-term goal is to determine mechanisms underlying invasive growth of human melanomas. Mutations in B-RAF are found in 50-70% of melanomas and mutant B-RAF activation of the MEK-ERK1/2 pathway is required for invasion and resistance to apoptosis. Additionally, fibronectin-integrin signaling co-operates with B-RAF to promote survival are poorly defined. The goals of this application are to determine roles and underlying mechanisms of B-RAF regulated targets in melanoma invasion and whether targeting of stromal fibronectin-integrin signaling, in combination with B-RAF, inhibits melanoma cell survival. In Specific Aim 1, we will test the hypothesis that B-RAF regulated Rho family GTPase, Rnd3, promotes melanoma cell invasion. We will utilize 3-D human skin reconstruct and in vivo intradermal injection models. Additionally, we will analyze effects on focal adhesion turnover in live cell imaging assays and invasion in vitro. In Specific Aim 2, we will determine the effect of expression of the forkhead transcription factor FOXD2 on melanoma cell invasion in 3-D, focal adhesion dynamics and B-RAF-regulated Rnd3 expression. In Specific Aim 3, we will utilize co-culture assays to determine the role of fibroblast-produced fibronectin on Akt activation and melanoma survival in a dermal microenvironment. Furthermore in this Aim, we will utilize genetic, antibody, and clinical grade inhibitor approaches will test for co-operation between av?3 integrins (which are up-regulated in melanoma progression) and mutant B-RAF in melanoma cell survival. We expect to identify new mechanisms underlying B-RAF regulation of invasive and survival properties in melanoma. At the completion of the proposed study, we expect to have identified mechanisms in tumor and stromal cells that regulate melanoma cell invasion and survival. Additionally, we expect to highlight combinatorial targeting of fibronectin-integrins with B-RAF inhibitors as a therapeutic strategy for the treatment of melanoma.
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