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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/801 |
| _version_ | 1797626586121371648 |
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| author | Carlos Peris-Torres María del Carmen Plaza-Calonge Raúl López-Domínguez Silvia Domínguez-García Antonio Barrientos-Durán Pedro Carmona-Sáez Juan Carlos Rodríguez-Manzaneque |
| author_facet | Carlos Peris-Torres María del Carmen Plaza-Calonge Raúl López-Domínguez Silvia Domínguez-García Antonio Barrientos-Durán Pedro Carmona-Sáez Juan Carlos Rodríguez-Manzaneque |
| author_sort | Carlos Peris-Torres |
| collection | DOAJ |
| 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 <i>ADAMTS1</i> exemplifies this dual role. In this work, we first confirmed a positive correlation of <i>ADAMTS1</i> with endothelial-like phenotype of human melanoma cells together with the finding of associated signatures, including key genes such as endothelial <i>CDH5</i>. Using a CRISPR-Cas9 approach, we observed that the inhibition of <i>ADAMTS1</i> 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 <i>ADAMTS1</i>-deficient tumors, the most relevant action implied the downregulation of endothelial <i>CDH5</i> in tumor cells, in association with stemness markers. Indeed, melanoma sphere assays also revealed a deficient commitment to form spheres in the absence of <i>ADAMTS1</i>, 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. |
| first_indexed | 2024-03-11T10:12:32Z |
| format | Article |
| id | doaj.art-2a1a1c1a452841aca582970bdbad3280 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T10:12:32Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2a1a1c1a452841aca582970bdbad32802023-11-16T14:25:22ZengMDPI AGCancers2072-66942020-03-0112480110.3390/cancers12040801Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor CellsCarlos Peris-Torres0María del Carmen Plaza-Calonge1Raúl López-Domínguez2Silvia Domínguez-García3Antonio Barrientos-Durán4Pedro Carmona-Sáez5Juan Carlos Rodríguez-Manzaneque6GENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainGENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, 114, 18016 Granada, SpainExtracellular 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 <i>ADAMTS1</i> exemplifies this dual role. In this work, we first confirmed a positive correlation of <i>ADAMTS1</i> with endothelial-like phenotype of human melanoma cells together with the finding of associated signatures, including key genes such as endothelial <i>CDH5</i>. Using a CRISPR-Cas9 approach, we observed that the inhibition of <i>ADAMTS1</i> 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 <i>ADAMTS1</i>-deficient tumors, the most relevant action implied the downregulation of endothelial <i>CDH5</i> in tumor cells, in association with stemness markers. Indeed, melanoma sphere assays also revealed a deficient commitment to form spheres in the absence of <i>ADAMTS1</i>, 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.https://www.mdpi.com/2072-6694/12/4/801ADAMTScancer stem cellendothelial-like phenotypeextracellular matrixvasculogenic mimicry |
| spellingShingle | Carlos Peris-Torres María del Carmen Plaza-Calonge Raúl López-Domínguez Silvia Domínguez-García Antonio Barrientos-Durán Pedro Carmona-Sáez Juan Carlos Rodríguez-Manzaneque Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells Cancers ADAMTS cancer stem cell endothelial-like phenotype extracellular matrix 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 |
| 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 | ADAMTS cancer stem cell endothelial-like phenotype extracellular matrix vasculogenic mimicry |
| url | https://www.mdpi.com/2072-6694/12/4/801 |
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