MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression

J Invest Dermatol. 2018 Jan;138(1):141-149. doi: 10.1016/j.jid.2017.05.038. Epub 2017 Sep 18.

Abstract

Melanoma cells share many biological properties with neural crest stem cells. Here we show that the homeodomain transcription factor MSX1, which is significantly correlated with melanoma disease progression, reprograms melanocytes and melanoma cells toward a neural crest precursor-like state. MSX1-reprogrammed normal human melanocytes express the neural crest marker p75 and become multipotent. MSX1 induces a phenotypic switch in melanoma, which is characterized by an oncogenic transition from an E-cadherin-high nonmigratory state toward a ZEB1-high invasive state. ZEB1 up-regulation is responsible for the MSX1-induced migratory phenotype in melanoma cells. Depletion of MSX1 significantly inhibits melanoma metastasis in vivo. These results show that neural crest-like reprogramming achieved by a single factor is a critical process for melanoma progression.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Transformation, Neoplastic / pathology*
  • Cellular Reprogramming / physiology*
  • Dermis / cytology
  • Dermis / pathology
  • Disease Progression
  • HEK293 Cells
  • Human Embryonic Stem Cells
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • MSX1 Transcription Factor / genetics
  • MSX1 Transcription Factor / physiology*
  • Melanocytes / pathology*
  • Melanoma / mortality
  • Melanoma / pathology*
  • Melanoma / secondary
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nerve Tissue Proteins / metabolism
  • Neural Crest / physiology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Nerve Growth Factor / metabolism
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology*
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • MSX1 Transcription Factor
  • MSX1 protein, human
  • NGFR protein, human
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, Nerve Growth Factor
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1