Primary Appointment

The focus of my laboratory is to study the molecular biology of melanoma metastasis. The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not very well defined.

We found that the highly metastatic cells do not express the transcriptional factor AP-2. Since AP-2 regulates the expression of MCAM/MUC18, c-KIT and MMP-2, and since other important genes involved in the progression of human melanoma such as E-cadherin, HER-2, VEGF, FAS/APO-1, bcl-2 and Kai-1, are also regulated by AP-2, we hypothesized that loss of AP-2 could be a “major switch” in the development of malignant melanoma. We were able to demonstrate that loss of AP-2 expression resulted in loss of c-KIT and upregulation of MUC18. Furthermore, re-introduction of AP-2 into the highly metastatic cells caused inhibition of tumor growth and significant reduction in their metastatic potential in nude mice. Using cDNA microchip, we recently identified the thrombin receptor PAR-1 to be a target for regulation by AP-2. We found that loss of AP-2 resulted in overexpression of PAR-1 in metastatic melanoma cells, which in turn contributes, to invasion and metastasis. Based on our data, we propose the notion that AP-2 serves a key regulator of melanoma metastasis. Overexpression of PAR-1 contributes to the metastatic phenotype by regulating connexin-43, Maspin, and MCAM/MUC18.

In other studies we have recently demonstrated that dominant-negative CREB can inhibit growth and metastasis of melanoma via regulation of MMP-2 and MUC18 gene expression. In addition, we also demonstrated that CREB and its associated proteins act as survival factors for human melanoma cells, thus, providing a mechanism, for the first time, on how overexpression of CREB in melanoma cells may contribute to the acquisition of the metastatic phenotype. CREB also regulates the expression of the tumor suppressor gene CYR61.

In recent studies, we found that PAF, which is secreted by cells in the tumor microenvironment, stimulates the phosphorylation and activation of CREB in metastatic melanoma cells. Based on our data on the involvement of MUC18 and IL-8 in the progression of human melanoma, we recently developed two fully humanized antibodies to target these molecules. Treatment of melanoma bearing nude mice with fully human IL-8 (ABX-IL-8) or fully human anti-MUC18 (ABX-MA1) reduced melanoma growth and inhibited their metastatic potential.

Last updated: 9/22/2009