Background: Melanoma is an extremely aggressive skin cancer, which represents a major public health problem in Australia and worldwide. Major challenges in the treatment of melanoma is its invasive capacity as well as its inherent plasticity and heterogeneity, allowing for treatment escape. While new treatments that block tumour growth are emerging, the identification of targetable mechanisms to inhibit metastatic spread has been slow. Epithelial-to-mesenchymal transition (EMT) is a hallmark event in the metastatic cascade conferring plasticity and invasive ability to cells.
Aim: We propose to exploit the phenotypic differences between the distinct cellular states of melanoma cells in culture to identify novel regulators of invasive switch so as to effectively block motility both in vitro and in vivo.
Methods and Results: We applied microarray-based gene expression data to distinguish subgroups of melanoma cells with distinct biological traits associated with different states of EMT. Epithelial-like cells were sessile, whereas mesenchymal-like were invasive. Invasive mesenchymal-like cell lines show up-regulation of N-cadherin, snail and thrombospondin-1, while proliferative epithelial-like cell lines are marked by expression of differentiation antigens like MelanA, Tyrosinase and E-cadherin. We have identified and validated 55 most invasive genes in 20 melanoma cell lines. To further identify if these genes are potential key players of invasion, we suppressed their expression with RNAi technology and tested their role in blocking melanoma invasion in matrigel coated boyden chambers. Next, we tested whether targeting these genes results in the abrogation of motility in vivo within the neural tube of embryonic chick model. Using this innovative embryonic avian model which mimics the spreading of melanoma cells will ensure the identification of disease relevant targets.
Conclusion: Integrating this in vivo system into our studies will enable us to gain a comprehensive understanding of the underlying cause of melanoma plasticity. This study will therefore aid in the identification of targets which may prevent metastasis and treatment escape.