Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium
| Autor: | Michael D. Onken, John A. Cooper, Kendall J. Blumer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Uveal Neoplasms
rac1 GTP-Binding Protein Endothelium Motility Cytoplasmic Streaming Biology Metastasis 03 medical and health sciences 0302 clinical medicine Blister Cell Movement Cell Line Tumor medicine Humans Pseudopodia Molecular Biology Melanoma 030304 developmental biology 0303 health sciences Transendothelial migration Tumor Suppressor Proteins Mesenchymal stem cell Transendothelial and Transepithelial Migration Cell Biology Articles medicine.disease eye diseases medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research GTP-Binding Protein alpha Subunits Gq-G11 rhoA GTP-Binding Protein Ubiquitin Thiolesterase Signal Transduction |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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