A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma

Br J Cancer. 2021 Aug;125(5):699-713. doi: 10.1038/s41416-021-01442-6. Epub 2021 Jun 25.


Background: Metastasis is a hallmark of cancer and responsible for most cancer deaths. Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and thus cancers' ability to metastasise. First anti-metastatic treatments have recently been approved.

Methods: We used bioinformatic analyses of publicly available melanoma databases. Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues.

Results: Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology.

Conclusions: We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Computational Biology / methods*
  • Humans
  • Male
  • Mass Spectrometry
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Mice
  • Myosin Type II / metabolism*
  • Neoplasm Metastasis
  • Protein Interaction Maps
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • Protein Kinase Inhibitors
  • rho-Associated Kinases
  • Myosin Type II
  • RhoA protein, mouse
  • rhoA GTP-Binding Protein