Abstract
Uveal melanoma arises in the eye, and it spreads to distant organs in almost half of patients, leading to a fatal outcome. To metastasize, uveal melanoma cells must transmigrate into and out of the microvasculature, crossing the monolayer of endothelial cells that separates the vessel lumen from surrounding tissues. We investigated how human uveal melanoma cells cross the endothelial cell monolayer, using a cultured cell system with primary human endothelial cell monolayers on hydrogel substrates. We found that uveal melanoma cells transmigrate by a novel and unexpected mechanism. Uveal melanoma cells intercalate into the endothelial cell monolayer and flatten out, assuming a shape and geometry similar to those of endothelial cells in the monolayer. After an extended period of time in the intercalated state, the uveal melanoma cells round up and migrate underneath the monolayer. VCAM is present on endothelial cells, and anti-VCAM antibodies slowed the process of intercalation. Depletion of BAP1, a known suppressor of metastasis in patients, increased the amount of transmigration of uveal melanoma cells in transwell assays; but BAP1 depletion did not affect the rate of intercalation, based on movies of living cells. Our results reveal a novel route of transendothelial migration for uveal melanoma cells, and they provide insight into the mechanism by which loss of BAP1 promotes metastasis.
Highlights
Melanomas are highly aggressive cancers that often metastasize and result in patient death [1]
We report the discovery that Uveal melanomas (UMs) cells transmigrate via a novel process that includes intercalation into the endothelial cells (ECs) monolayer, after which they migrate under the monolayer to invade interstitial tissue
We find that this process requires VCAM-mediated adhesion between UM cells and ECs and that loss of the metastasis suppressor BAP1 enhances transendothelial migration (TEM)
Summary
Melanomas are highly aggressive cancers that often metastasize and result in patient death [1]. For melanomas that arise in the pigmented uveal layers of the eye, almost half of patients develop fatal metastatic disease, even after the tumorbearing eye is surgically removed [2]. Transendothelial Migration by Melanoma Cells into the vitreous space [3]. The highly vascular nature of the uvea provides a ready outlet for the spread of UM cells to distant organs through the bloodstream [4]. The spread of UM cancer cells by the hematogenous route is critical to the morbidity and mortality of the disease, and it would be important to understanding the mechanism by which UM cells cross the endothelial barrier as they enter and exit the bloodstream
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