Expression signatures of early-stage and advanced medaka melanomas

Melanoma is one of the most aggressive tumors with a very low survival rate once metastasized. The incidence of newly detected cases increases every year suggesting the necessity of development and application of innovative treatment strategies. Human melanoma develops from melanocytes localized in the epidermis of the skin to malignant tumors because of deregulated effectors influencing several molecular pathways. Despite many advances in describing the molecular changes accompanying melanoma formation, many critical and clinically relevant molecular features of the transformed pigment cells and the underlying mechanisms are largely unknown. To contribute to a better understanding of the molecular processes of melanoma formation, we use a transgenic medaka melanoma model that is well suited for the investigation of melanoma tumor development because fish and human melanocytes are both localized in the epidermis. The purpose of our study was to gain insights into melanoma development from the first steps of tumor formation up to melanoma progression and to identify gene expression patterns that will be useful for monitoring treatment effects in drug screening approaches. Comparing transcriptomes from juvenile fish at the tumor initiating stage with nevi and advanced melanoma of adults, we identified stage specific expression signatures and pathways that are characteristic for the development of medaka melanoma, and are also found in human malignancies.

黑色素瘤（melanoma）是侵袭性最强的恶性肿瘤之一，一旦发生转移，患者生存率极低。近年来新发确诊病例数逐年攀升，凸显了开发并应用创新治疗策略的必要性。人类黑色素瘤源于皮肤表皮（epidermis）层的黑素细胞（melanocytes），由于影响多种分子通路（molecular pathways）的效应因子（effectors）失调，最终恶变为恶性肿瘤。尽管学界在阐明黑色素瘤发生伴随的分子改变方面已取得诸多进展，但恶变色素细胞的诸多关键临床相关分子特征及其潜在机制仍在很大程度上未被解析。为了更好地理解黑色素瘤发生的分子过程，本研究采用了转基因青鳉（medaka）黑色素瘤模型——由于鱼类与人类的黑素细胞均定位于表皮层，该模型非常适合用于黑色素瘤发生发展的研究。本研究旨在从肿瘤发生的初始阶段到黑色素瘤进展全程，解析其发生发展机制，并鉴定可用于药物筛选中监测治疗效果的基因表达谱。通过对比肿瘤起始阶段幼鱼、成年鱼黑素细胞痣（nevi）及晚期黑色素瘤的转录组（transcriptomes），本研究鉴定出了青鳉黑色素瘤发生发展特有的阶段特异性表达特征与通路，且这些特征与通路同样存在于人类恶性肿瘤中。