@misc{10481/62453,
year = {2020},
month = {3},
url = {http://hdl.handle.net/10481/62453},
abstract = {Extracellular matrix remodeling within the tumor microenvironment has been recognized
as a relevant dynamic framework during tumor growth. However, research on proteases that trigger
this remodeling keeps revealing a wide range of actions including both pro- and anti-tumorigenic.
The extracellular protease ADAMTS1 exemplifies this dual role. In this work, we first confirmed
a positive correlation of ADAMTS1 with endothelial-like phenotype of human melanoma cells
together with the finding of associated signatures, including key genes such as endothelial CDH5.
Using a CRISPR-Cas9 approach, we observed that the inhibition of ADAMTS1 in an aggressive
uveal melanoma model compromised its endothelial-like properties, and more importantly, caused a
robust blockade on the progression of tumor xenografts. Although vasculature emerged affected
in ADAMTS1-deficient tumors, the most relevant action implied the downregulation of endothelial
CDH5 in tumor cells, in association with stemness markers. Indeed, melanoma sphere assays also
revealed a deficient commitment to form spheres in the absence of ADAMTS1, directly correlating
with stemness markers and, remarkably, also with CDH5. Finally, taking advantage of advanced
bioinformatics tools and available public data of uveal melanomas, we disclosed new prognosis
factors, including endothelial elements and ADAMTS proteases. Our findings support the key role of
ADAMTS proteases for uveal melanoma development since earlier stages, modulating the complex
crosstalk between extracellular matrix and the induction of stemness and endothelial-like features.
To our knowledge, this is the first report that supports the development of therapeutic targets on the
extracellular matrix to overcome uveal melanoma.},
organization = {This research was supported by Ministerio de Economía y Competitividad and Instituto de Salud
Carlos III from Spain, co-financed by FEDER (PI16/00345 to JCRM) and from Consejería de Salud de la Junta de
Andalucía (OH-0028-2018, PE-0225-2018).},
publisher = {MDPI},
keywords = {ADAMTS},
keywords = {Cancer stem cell},
keywords = {Endothelial-like phenotype},
keywords = {Extracellular-matrix},
keywords = {Vasculogenic mimicry},
title = {Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells},
doi = {doi:10.3390/cancers12040801},
author = {Peris Torres, Carlos and Plaza Calonge, María del Carmen and López Domínguez, Raúl and Domínguez García, Silvia and Barrientos Durán, Antonio and Carmona Sáez, Pedro and Rodríguez-Manzaneque, Juan Carlos},
}