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bioRxiv · 10.1101/2020.03.18.997627

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

Onken, M. D.·Cooper, J. A.
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Abstract

Uveal melanomas (UM) 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, notably transendothelial migration (TEM), is a key step in formation of metastases. UM cells execute TEM via a stepwise process of intercalation into the endothelial monolayer involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations in Gq/11, which activate TRIO, a guanine nucleotide exchange factor (GEF) for RhoA and Rac1. Pharmacologic inhibition of Gq/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 also inhibited mesenchymal motility, but invasion was less affected; in this case, the amoeboid blebbing behavior of the cells led to transmigration without intercalation, a direct mechanism similar to that of immune cells. BAP1-deficient (+/-) UM subclones displayed motility behavior and increased levels of TEM, similar to effects of RhoA inhibitors. We conclude that RhoA and Rac1 signaling pathways, downstream of oncogenic Gq/11, combine with pathways regulated by BAP1 to control the motility and transmigration of UM cells.

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Onken, M. D., Cooper, J. A.. 2020-03-20. Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium. https://doi.org/10.1101/2020.03.18.997627

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