Despite advances in therapeutics, the progression of melanoma to metastasis still confers a poor outcome to patients. Nevertheless, there is a scarcity of biological models to understand cellular and molecular changes taking place along disease progression. Here, we characterized the transcriptome profiles of a multi-stage murine model of melanoma progression comprising a nontumorigenic melanocyte lineage (melan-a), premalignant melanocytes (4C), nonmetastatic (4C11-) and metastasis-prone (4C11+) melanoma cells. Clustering analyses have grouped the 4 cell lines according to their differentiated (melan-a and 4C11+) or undifferentiated/“mesenchymal-like” (4C and 4C11-) morphologies, suggesting dynamic gene expression patterns associated with the transition between these phenotypes. The cell plasticity observed in the murine melanoma progression model was corroborated by molecular markers described during stepwise human melanoma differentiation, as the differentiated cell lines in our model exhibit upregulation of transitory and melanocytic markers, whereas “mesenchymal-like” cells show increased expression of undifferentiated and neural crest-like markers. Sets of differentially expressed genes (DEGs) were detected at each transition step of tumor progression, and transcriptional signatures related to malignancy, metastasis and epithelial-to-mesenchymal transition were identified. Finally, DEGs were mapped to their human orthologs and evaluated in uni- and multivariate survival analyses using gene expression and clinical data of 703 drug-naïve primary melanoma patients, revealing several independent candidate prognostic markers. Altogether, these results provide novel insights into the molecular mechanisms underlying the phenotypic switch taking place during melanoma progression, reveal potential drug targets and prognostic biomarkers, and corroborate the translational relevance of this unique sequential model of melanoma progression.

尽管治疗方法取得了进步，但黑色素瘤进展到转移仍然会给患者带来不良的结果。然而，缺乏了解疾病进展过程中发生的细胞和分子变化的生物模型。在这里，我们表征了黑色素瘤进展的多阶段小鼠模型的转录组谱，包括非致瘤性黑色素细胞谱系 (melan-a)、癌前黑色素细胞 (4C)、非转移性 (4C11-) 和易转移 (4C11+) 黑色素瘤细胞。聚类分析根据它们的分化（melan-a 和 4C11+）或未分化/“间充质样”（4C 和 4C11-）形态对 4 种细胞系进行分组，表明与这些表型之间的转变相关的动态基因表达模式。在小鼠黑色素瘤进展模型中观察到的细胞可塑性得到了人类黑色素瘤逐步分化过程中描述的分子标记的证实，因为我们模型中的分化细胞系表现出暂时性和黑色素细胞标记的上调，而“间充质样”细胞显示未分化的表达增加和神经嵴样标记物。在肿瘤进展的每个过渡步骤中检测到一组差异表达基因 (DEG)，并鉴定出与恶性肿瘤、转移和上皮间质转化相关的转录特征。最后，DEG 被映射到他们的人类直系同源物，并使用 703 名未接受药物治疗的原发性黑色素瘤患者的基因表达和临床数据在单变量和多变量生存分析中进行评估，揭示了几个独立的候选预后标志物。总之，这些结果为黑色素瘤进展过程中发生的表型转换的分子机制提供了新的见解，揭示了潜在的药物靶点和预后生物标志物，并证实了这种独特的黑色素瘤进展顺序模型的转化相关性。