Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis
Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis
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DOI：
10.1038/s41467-019-14085-2
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发表时间：
2020-01-16
影响因子：
16.6
通讯作者：
Mishra, Pravin J.
中科院分区：
文献类型：
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作者：
Marie, Kerrie L.;Sassano, Antonella;Mishra, Pravin J.
皮肤恶性黑色素瘤是一种侵袭性黑色素细胞癌症，具有很强的转移倾向。我们假设黑色素瘤细胞通过采用胚胎样表型获得转移能力，并且谱系方法将揭示转移性黑色素瘤生物学。使用基因工程小鼠模型生成丰富的黑素细胞转录组数据集，我们识别了黑素细胞特异性基因，其表达有助于转移能力，并得出预测患者生存的 43 基因特征。我们鉴定出一种黑色素细胞基因 KDELR3，该基因的缺失会损害实验性转移。相比之下，KDELR1 缺陷会增强转移，这是逆行转运蛋白 KDELR 家族内不同疾病病因的第一个例子。我们证明 KDELR3 调节转移抑制因子 KAI1，并报告与 E3 泛素蛋白连接酶 gp78（KAI1 降解调节因子）的相互作用。我们的工作表明，可以挖掘黑色素细胞转录组来揭示黑色素瘤治疗的靶向途径。
Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.