WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Nat Commun. 2020 Oct 20;11(1):5315. doi: 10.1038/s41467-020-18951-2.

Abstract

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Female
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Humans
  • Male
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Myosin Type II / genetics
  • Myosin Type II / metabolism
  • Neoplasm Invasiveness
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism

Substances

  • Frizzled Receptors
  • Fzd7 protein, mouse
  • Microfilament Proteins
  • Wnt Proteins
  • Wnt11 protein, mouse
  • Rock1 protein, mouse
  • rho-Associated Kinases
  • Daam1 protein, mouse
  • Myosin Type II
  • rho GTP-Binding Proteins