Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced 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 novel targetable pathways for melanoma therapy.