Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

Nat Commun. 2020 Jan 16;11(1):333. doi: 10.1038/s41467-019-14085-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Endoplasmic Reticulum
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Kangai-1 Protein / genetics
  • Kangai-1 Protein / metabolism
  • Lung / pathology
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Melanoma, Cutaneous Malignant
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / genetics
  • Neoplasms, Second Primary / pathology
  • Phenotype
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Transcriptome*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Cd82 antigen, mouse
  • KDELR1 protein, mouse
  • Kangai-1 Protein
  • Receptors, Peptide
  • Ubiquitin-Protein Ligases