Integrated melanoma/melanoblast transcriptomics identifies novel metastasis regulators: A role for ER stress

Cutaneous malignant melanoma is often highly aggressive, metastatic, and resistant to current therapeutic approaches. Since the behavior of metastatic melanoma cells can phenocopy that of embryonic melanoblasts, we here employed a whole genome transcriptomic approach to test if melanoma’s penchant for metastasis can be attributed to broad re-initiation of pathways otherwise restricted predominantly to embryos. We used a genetically engineered mouse designed to fluorescently label melanocytic cells to purify developmentally-staged melanoblasts and generate rich datasets of their transcriptomes. We demonstrate that these datasets represent discrete subgroups of metastatic melanoma patients, and can be used to produce a gene signature that serves as a biomarker predicting patient survival. Functional studies confirmed that expression of melanoblast-specific genes can enhance mouse and human melanoma metastasis, including the poorly characterized retrotransport chaperone KDELR3, highlighting the importance of Endoplasmic Reticulum homeostasis in metastasis. We link KDELR3 with the E3 ubiquitin-protein ligase gp78, through which it helps to regulate both mitochondrial metabolism and stability of the metastasis suppressor, KAI1. Our work identifies a metastasis-development axis, providing novel insights into mechanisms of melanoma progression, and a source of untested pathways for treating metastatic melanoma.