Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/5/1200 |
| _version_ | 1797475475999686656 |
|---|---|
| author | Alberto Vázquez-Naharro José Bustos-Tauler Alfredo Floristán Lourdes Yuste Sara S. Oltra Antònia Vinyals Gema Moreno-Bueno Àngels Fabra Francisco Portillo Amparo Cano Patricia G. Santamaría |
| author_facet | Alberto Vázquez-Naharro José Bustos-Tauler Alfredo Floristán Lourdes Yuste Sara S. Oltra Antònia Vinyals Gema Moreno-Bueno Àngels Fabra Francisco Portillo Amparo Cano Patricia G. Santamaría |
| author_sort | Alberto Vázquez-Naharro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:45:38Z |
| format | Article |
| id | doaj.art-617f56d8f483488cba6fc09240bebe19 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:45:38Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-617f56d8f483488cba6fc09240bebe192023-11-23T22:47:24ZengMDPI AGCancers2072-66942022-02-01145120010.3390/cancers14051200Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and SurvivalAlberto Vázquez-Naharro0José Bustos-Tauler1Alfredo Floristán2Lourdes Yuste3Sara S. Oltra4Antònia Vinyals5Gema Moreno-Bueno6Àngels Fabra7Francisco Portillo8Amparo Cano9Patricia G. Santamaría10Departamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainOncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainOncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainMalignant 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.https://www.mdpi.com/2072-6694/14/5/1200LOXL3melanomamelanoma metastasisgenetic mouse modelEMTcellular plasticity |
| spellingShingle | Alberto Vázquez-Naharro José Bustos-Tauler Alfredo Floristán Lourdes Yuste Sara S. Oltra Antònia Vinyals Gema Moreno-Bueno Àngels Fabra Francisco Portillo Amparo Cano Patricia G. Santamaría Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival Cancers LOXL3 melanoma melanoma metastasis genetic mouse model EMT cellular plasticity |
| title | 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_short | Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival |
| title_sort | loxl3 promotes melanoma progression and dissemination influencing cell plasticity and survival |
| topic | LOXL3 melanoma melanoma metastasis genetic mouse model EMT cellular plasticity |
| url | https://www.mdpi.com/2072-6694/14/5/1200 |
| work_keys_str_mv | AT albertovazqueznaharro loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT josebustostauler loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT alfredofloristan loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT lourdesyuste loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT sarasoltra loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT antoniavinyals loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT gemamorenobueno loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT angelsfabra loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT franciscoportillo loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT amparocano loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival AT patriciagsantamaria loxl3promotesmelanomaprogressionanddisseminationinfluencingcellplasticityandsurvival |