Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival

Malignant melanoma is the most lethal skin cancer due to its aggressive clinical behavior and therapeutic resistance. A comprehensive knowledge of the molecular mechanisms underlying melanoma progression is urgently needed to improve the survival of melanoma patients. Phenotypic plasticity of melano...

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Autores: Vázquez Naharro, Alberto, Bustos Tauler, José, Floristán, Alfredo, Yuste, Lourdes, Oltra, Sara S., Vinyals, Antònia, Moreno Bueno, Gema, Fabra Fres, Àngels, Portillo, Francisco, Cano, Amparo, Santamaría, Patricia G.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/185138
Acesso em linha:https://hdl.handle.net/2445/185138
Access Level:acceso abierto
Palavra-chave:Melanoma
Metàstasi
Metastasis
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spelling Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and SurvivalVázquez Naharro, AlbertoBustos Tauler, JoséFloristán, AlfredoYuste, LourdesOltra, Sara S.Vinyals, AntòniaMoreno Bueno, GemaFabra Fres, ÀngelsPortillo, FranciscoCano, AmparoSantamaría, Patricia G.MelanomaMetàstasiMelanomaMetastasisMalignant melanoma is the most lethal skin cancer due to its aggressive clinical behavior and therapeutic resistance. A comprehensive knowledge of the molecular mechanisms underlying melanoma progression is urgently needed to improve the survival of melanoma patients. Phenotypic plasticity of melanoma cells has emerged as a key process in melanomagenesis and therapy resistance. This phenotypic plasticity is sustained by an epithelial-to-mesenchymal (EMT)-like program that favors multiple intermediate states and allows adaptation to changing microenvironments along melanoma progression. Given the essential role of lysyl oxidase-like 3 (LOXL3) in human melanoma cell survival and its contribution to EMT, we generated mice with conditional melanocyte-specific targeting of Loxl3, concomitant to Braf activation and Pten deletion. Our results supported a key role of Loxl3 for melanoma progression, metastatic dissemination, and genomic stability, and supported its contribution to melanoma phenotypic plasticity by modulating the expression of several EMT transcription factors (EMT-TFs). 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.MDPI AG2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/185138Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/cancers14051200Cancers, 2022, vol. 14, num. 5https://doi.org/10.3390/cancers14051200cc by (c) Vázquez Naharro, Alberto et al, 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1851382026-05-27T06:46:51Z
dc.title.none.fl_str_mv Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
title Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
spellingShingle Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
Vázquez Naharro, Alberto
Melanoma
Metàstasi
Melanoma
Metastasis
title_short Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
title_full Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
title_fullStr Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
title_full_unstemmed Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
title_sort Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
dc.creator.none.fl_str_mv Vázquez Naharro, Alberto
Bustos Tauler, José
Floristán, Alfredo
Yuste, Lourdes
Oltra, Sara S.
Vinyals, Antònia
Moreno Bueno, Gema
Fabra Fres, Àngels
Portillo, Francisco
Cano, Amparo
Santamaría, Patricia G.
author Vázquez Naharro, Alberto
author_facet Vázquez Naharro, Alberto
Bustos Tauler, José
Floristán, Alfredo
Yuste, Lourdes
Oltra, Sara S.
Vinyals, Antònia
Moreno Bueno, Gema
Fabra Fres, Àngels
Portillo, Francisco
Cano, Amparo
Santamaría, Patricia G.
author_role author
author2 Bustos Tauler, José
Floristán, Alfredo
Yuste, Lourdes
Oltra, Sara S.
Vinyals, Antònia
Moreno Bueno, Gema
Fabra Fres, Àngels
Portillo, Francisco
Cano, Amparo
Santamaría, Patricia G.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Melanoma
Metàstasi
Melanoma
Metastasis
topic Melanoma
Metàstasi
Melanoma
Metastasis
description Malignant melanoma is the most lethal skin cancer due to its aggressive clinical behavior and therapeutic resistance. A comprehensive knowledge of the molecular mechanisms underlying melanoma progression is urgently needed to improve the survival of melanoma patients. Phenotypic plasticity of melanoma cells has emerged as a key process in melanomagenesis and therapy resistance. This phenotypic plasticity is sustained by an epithelial-to-mesenchymal (EMT)-like program that favors multiple intermediate states and allows adaptation to changing microenvironments along melanoma progression. Given the essential role of lysyl oxidase-like 3 (LOXL3) in human melanoma cell survival and its contribution to EMT, we generated mice with conditional melanocyte-specific targeting of Loxl3, concomitant to Braf activation and Pten deletion. Our results supported a key role of Loxl3 for melanoma progression, metastatic dissemination, and genomic stability, and supported its contribution to melanoma phenotypic plasticity by modulating the expression of several EMT transcription factors (EMT-TFs). 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/185138
url https://hdl.handle.net/2445/185138
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/cancers14051200
Cancers, 2022, vol. 14, num. 5
https://doi.org/10.3390/cancers14051200
dc.rights.none.fl_str_mv cc by (c) Vázquez Naharro, Alberto et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Vázquez Naharro, Alberto et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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