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Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis.
Nature Communications ( IF 16.6 ) Pub Date : 2020-01-16 , DOI: 10.1038/s41467-019-14085-2
Kerrie L Marie 1 , Antonella Sassano 1 , Howard H Yang 1 , Aleksandra M Michalowski 1 , Helen T Michael 1 , Theresa Guo 1, 2 , Yien Che Tsai 3 , Allan M Weissman 3 , Maxwell P Lee 1 , Lisa M Jenkins 4 , M Raza Zaidi 5 , Eva Pérez-Guijarro 1 , Chi-Ping Day 1 , Kris Ylaya 6 , Stephen M Hewitt 6 , Nimit L Patel 7 , Heinz Arnheiter 8 , Sean Davis 9 , Paul S Meltzer 9 , Glenn Merlino 1 , Pravin J Mishra 1, 10
Affiliation  

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.

中文翻译:

黑色素母细胞转录组分析揭示促进黑色素瘤转移的途径。

皮肤恶性黑色素瘤是侵袭性黑色素细胞癌,具有很强的转移倾向。我们假设黑色素瘤细胞通过采用类似胚胎的表型来获得转移能力,并且沿袭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来生成丰富的黑素母细胞转录组数据集,我们确定了黑素母细胞特异的基因,其表达有助于转移能力,并获得了预测患者生存的43个基因的签名。我们确定黑素细胞基因,KDELR3,其损失损害实验性转移。相反,KDELR1缺乏症会促进转移,这是逆行转运蛋白KDELR家族中不同病因的第一个例子。我们证明,KDELR3调节转移抑制因子KAI1,并报告了它与KAI1降解调节剂E3泛素蛋白连接酶gp78的相互作用。我们的工作表明,可以挖掘黑色素细胞转录组,以发现用于黑色素瘤治疗的靶向途径。
更新日期:2020-01-16
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