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Nat Commun. 2020 Jan 16;11(1):333
Authors: Marie KL, Sassano A, Yang HH, Michalowski AM, Michael HT, Guo T, Tsai YC, Weissman AM, Lee MP, Jenkins LM, Zaidi MR, Pérez-Guijarro E, Day CP, Ylaya K, Hewitt SM, Patel NL, Arnheiter H, Davis S, Meltzer PS, Merlino G, Mishra PJ
Abstract
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.
PMID: 31949145 [PubMed - in process]
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