Abstract 4856: Using embryonic melanoblast transcriptome analysis to identify novel mechanisms promoting metastatic melanoma
Authors: Pravin J. Mishra, Theresa Guo, Raza Zaidi, Sean Davis, Heinz Arnheiter, Robert L. Walker, Paul Meltzer, Glenn Merlino
Journal: Cancer Research (2012)

Abstract Melanomas are among the most aggressive of cancers, especially in their ability to metastasize. Although melanoma only makes up &amp;lt;6% of all skin cancers, it contributes to over 70% of skin cancer deaths. 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 melanoblast developmental signature to reveal the intimate connection between tumorigenesis and developmental processes. While this theory is largely unproven, there are mechanistic links between the processes regulating development and malignancy. Other studies have identified common pathways between embryonic development and cancer. For instance, the Wnt pathway, in particular β-catenin signaling, has been identified as both a key regulator of cell fate during development and overactive in several malignancies including melanoma. We have, for the first time, using next generation RNA-sequencing, 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 see the overall classes of gene expression behavior and to identify and characterize genesets whose expression is common and equally important to melanomagenic and developmental processes, a heat map was generated using the top 1000 most variable genes. Furthermore, a gene list was shortlisted based on compared levels of expression. From that a distinct group was identified and found to be related to early neural expression, epigenetic regulation, collagens, G-protein coupled receptors and calcium regulators. As we were interested in dominant oncogenic metastatic lesions, we favored the genes that were expressed highly in embryos but not in differentiated melanocytes. Fold change increase and fold change decrease were calculated relative to earlier embryonic readout with a cut off value of α10-fold. By using a novel approach to filter genes expressed highly in embryonic melanocytes and poorly in differentiated melanocytes from the 1000 most variable genes, we selected the top 50 genes and further screened those using mouse and human melanoma cell lines relative to melanocytes. This extensive genomic comparative analysis has identified and validated a dozen potential oncofetal genes that are highly expressed in embryonic melanoblasts as well as metastatic melanoma cell lines relative to adult differentiated melanocytes. In this project, we propose to identify and characterize gene sets whose expression is common and equally important to both melanomagenesis and melanoblast developmental processes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4856. doi:1538-7445.AM2012-4856