Cargando…

Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells

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 p...

Descripción completa

Detalles Bibliográficos
Autores principales: Peris-Torres, Carlos, Plaza-Calonge, María del Carmen, López-Domínguez, Raúl, Domínguez-García, Silvia, Barrientos-Durán, Antonio, Carmona-Sáez, Pedro, Rodríguez-Manzaneque, Juan Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226337/
https://www.ncbi.nlm.nih.gov/pubmed/32230715
http://dx.doi.org/10.3390/cancers12040801
_version_ 1783534263620075520
author Peris-Torres, Carlos
Plaza-Calonge, María del Carmen
López-Domínguez, Raúl
Domínguez-García, Silvia
Barrientos-Durán, Antonio
Carmona-Sáez, Pedro
Rodríguez-Manzaneque, Juan Carlos
author_facet Peris-Torres, Carlos
Plaza-Calonge, María del Carmen
López-Domínguez, Raúl
Domínguez-García, Silvia
Barrientos-Durán, Antonio
Carmona-Sáez, Pedro
Rodríguez-Manzaneque, Juan Carlos
author_sort Peris-Torres, Carlos
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7226337
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72263372020-05-18 Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells Peris-Torres, Carlos Plaza-Calonge, María del Carmen López-Domínguez, Raúl Domínguez-García, Silvia Barrientos-Durán, Antonio Carmona-Sáez, Pedro Rodríguez-Manzaneque, Juan Carlos Cancers (Basel) Article 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. MDPI 2020-03-27 /pmc/articles/PMC7226337/ /pubmed/32230715 http://dx.doi.org/10.3390/cancers12040801 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Peris-Torres, Carlos
Plaza-Calonge, María del Carmen
López-Domínguez, Raúl
Domínguez-García, Silvia
Barrientos-Durán, Antonio
Carmona-Sáez, Pedro
Rodríguez-Manzaneque, Juan Carlos
Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title_full Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title_fullStr Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title_full_unstemmed Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title_short Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells
title_sort extracellular protease adamts1 is required at early stages of human uveal melanoma development by inducing stemness and endothelial-like features on tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226337/
https://www.ncbi.nlm.nih.gov/pubmed/32230715
http://dx.doi.org/10.3390/cancers12040801
work_keys_str_mv AT peristorrescarlos extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT plazacalongemariadelcarmen extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT lopezdominguezraul extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT dominguezgarciasilvia extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT barrientosduranantonio extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT carmonasaezpedro extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells
AT rodriguezmanzanequejuancarlos extracellularproteaseadamts1isrequiredatearlystagesofhumanuvealmelanomadevelopmentbyinducingstemnessandendotheliallikefeaturesontumorcells