Melanoma is among the most aggressive of cancers in its ability to metastasize. Although melanoma makes up <6% of all skin cancers, it contributes to over 70% of skin cancer deaths. There is no other tumor type that consistently gains metastatic potential in a matter of millimeters. However, the genes and pathways involved in this deadly manifestation remain elusive. The enhanced ability of melanoma cells to metastasize is reminiscent of the innate propensity of melanoblasts to migrate for long distances during embryonic development - from the neural crest to the eventual niche across the skin of the whole body. Once transformed, melanoma cells mimic migratory and growth capability similar to that of the embryonic melanoblasts. Therefore we hypothesize that late stage metastatic melanoma can exploit pathways employed by embryonic melanoblasts to achieve a more aggressive malignant phenotype.

In the present study, we paint a novel picture of the oncological landscape based on the mouse melanoblast signature to reveal an intimate connection between tumorigenesis and developmental processes. We have, for the first time isolated and sequenced the transcriptomes of murine embryonic melanoblasts at several key representative developmental stages utilizing a newly developed genetically engineered mouse model with melanocyte-specific GFP expression. To uncover the overall classes of gene expression and to identify and characterize genesets whose expression is common and equally important to melanomagenic and developmental processes, a heat-map of the top 1000 most variable developmental genes was generated, and then shortlisted based on compared levels of expression in human and mouse metastatic melanomas and a relationship with melanoma patient survival data. A series of bioinformatics and meta-analyses led us to identify a small number of candidate genes. The resulting gene set was found to be related to early neural expression, epigenetic regulation, collagens, G-protein coupled receptors and calcium regulators. As a final step toward the identification and characterization of genes whose expression is common and equally important to both melanoma metastasis and melanoblast developmental processes, we are determining the consequences of RNAi-based knockdown on experimental metastasis potential in mouse models. Developmental genes that regulate melanoma metastatic behavior will be fully characterized. This approach should facilitate identification of novel therapeutic targets for melanoma treatment and diagnosis. Our study will attempt to provide insight into elements of melanocyte development that might prime them for metastasis in future malignancies. Pathways parallel between embryonic and metastatic melanoma cells will be identified and validated, offering both mechanistic and prognostic significance to our understanding of this fatal disease.

Citation Format: Pravin J. Mishra, Theresa Guo, Raza Zaidi, Sean Davis, Heinz Arnheiter, William C. Reinhold, Paul Meltzer, Glenn Merlino. Using embryonic melanoblast transcriptome analysis to identify novel mechanisms promoting metastatic melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2994. doi:10.1158/1538-7445.AM2013-2994