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Título: | Loxl3 promotes melanoma progression and dissemination influencing cell plasticity and survival |
Autor: | Vázquez-Naharro, Alberto CSIC ORCID; Bustos-Tauler, José CSIC; Floristán, Alfredo CSIC ORCID; Yuste Pérez, Lourdes CSIC; Oltra, Sara S. CSIC; Vinyals, Antònia; Moreno-Bueno, Gema CSIC ORCID; Fabra, Àngels; García del Portillo, Francisco CSIC ORCID ; Cano, Amparo CSIC; Santamaría, Patricia G. CSIC ORCID | Palabras clave: | LOXL3 Melanoma Melanoma metastasis Genetic mouse model EMT Cellular plasticity SNAIL1 PRRX1 Phenotype switching |
Fecha de publicación: | 2022 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | Cancers 14(5): 1200 (2022) | Resumen: | Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs relies on phenotypic plasticity of melanoma cells, orchestrated by EMT-TFs and microphthalmia-associated TF (MITF). Recently, melanoma phenotypic switching has been proposed to uphold context-dependent intermediate cell states benefitting malignancy. LOXL3 (lysyl oxidase-like 3) promotes EMT and has a key role in human melanoma cell survival and maintenance of genomic integrity. To further understand the role of Loxl3 in melanoma, we generated a conditional Loxl3-knockout (KO) melanoma mouse model in the context of BrafV600E-activating mutation and Pten loss. Melanocyte-Loxl3 deletion increased melanoma latency, decreased tumor growth, and reduced lymph node metastatic dissemination. Complementary in vitro and in vivo studies in mouse melanoma cells confirmed Loxl3’s contribution to melanoma progression and metastasis, in part by modulating phenotypic switching through Snail1 and Prrx1 EMT-TFs. Importantly, a novel LOXL3-SNAIL1-PRRX1 axis was identified in human melanoma, plausibly relevant to melanoma cellular plasticity. These data reinforced the value of LOXL3 as a therapeutic target in melanoma. | Versión del editor: | http://dx.doi.org/10.3390/cancers14051200 | URI: | http://hdl.handle.net/10261/283915 | DOI: | 10.3390/cancers14051200 | Identificadores: | doi: 10.3390/cancers14051200 e-issn: 2072-6694 |
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Loxl3 Promotes Melanoma_Vázquez_PV_Art2022.pdf | 5,89 MB | Adobe PDF | Visualizar/Abrir |
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