Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium

Mol Biol Cell. 2021 Mar 1;32(5):413-421. doi: 10.1091/mbc.E20-04-0241. Epub 2021 Jan 6.


Uveal melanomas (UMs) are malignant cancers arising from the pigmented layers of the eye. UM cells spread through the bloodstream, and circulating UM cells are detectable in patients before metastases appear. Extravasation of UM cells is necessary for formation of metastases, and transendothelial migration (TEM) is a key step in extravasation. UM cells execute TEM via a stepwise process involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations that activate Gαq/11, and this activates TRIO, a guanine nucleotide exchange factor for RhoA and Rac1. We found that pharmacologic inhibition of Gαq/11 in UM cells reduced TEM. Inhibition of the RhoA pathway blocked amoeboid motility but led to enhanced TEM; in contrast, inhibition of the Rac1 pathway decreased mesenchymal motility and reduced TEM. Inhibition of Arp2/3 complex allowed cells to transmigrate without intercalation, a direct mechanism similar to the one often displayed by immune cells. BAP1-deficient (+/-) UM subclones displayed motility behavior and increased levels of TEM, similar to the effects of RhoA inhibitors. We conclude that RhoA and Rac1 signaling pathways, downstream of oncogenic Gαq/11, combine with pathways regulated by BAP1 to control the motility and transmigration of UM cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blister / metabolism
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Cytoplasmic Streaming / physiology
  • Endothelium / metabolism
  • Endothelium / pathology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Pseudopodia / metabolism
  • Signal Transduction / genetics
  • Transendothelial and Transepithelial Migration / physiology*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / metabolism
  • Uveal Neoplasms / metabolism*
  • Uveal Neoplasms / pathology
  • rac1 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / metabolism


  • BAP1 protein, human
  • RAC1 protein, human
  • Tumor Suppressor Proteins
  • RHOA protein, human
  • Ubiquitin Thiolesterase
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein

Supplementary concepts

  • Uveal melanoma