Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation
The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of...
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| Format: | Article |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13715 |
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| author | Kimberley McGrail Elena González‐Sánchez Paula Granado‐Martínez Roberto Orsenigo Yuxin Ding Berta Ferrer Javier Hernández‐Losa Iván Ortega Juan Martín‐Caballero Eva Muñoz‐Couselo Vicente García‐Patos Juan A. Recio |
| author_facet | Kimberley McGrail Elena González‐Sánchez Paula Granado‐Martínez Roberto Orsenigo Yuxin Ding Berta Ferrer Javier Hernández‐Losa Iván Ortega Juan Martín‐Caballero Eva Muñoz‐Couselo Vicente García‐Patos Juan A. Recio |
| author_sort | Kimberley McGrail |
| collection | DOAJ |
| description | The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1‐depleted mice compared with BrafV600E‐irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1‐null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural‐like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural‐like dedifferentiation. |
| format | Article |
| id | doaj-art-3b9f3d367e024f8e9fb98b134d7a952d |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-3b9f3d367e024f8e9fb98b134d7a952d2025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119232934310.1002/1878-0261.13715Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiationKimberley McGrail0Elena González‐Sánchez1Paula Granado‐Martínez2Roberto Orsenigo3Yuxin Ding4Berta Ferrer5Javier Hernández‐Losa6Iván Ortega7Juan Martín‐Caballero8Eva Muñoz‐Couselo9Vicente García‐Patos10Juan A. Recio11Biomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainBiomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainBiomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainBiomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainBiomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainAnatomy Pathology Department Vall d'Hebron Hospital‐UAB Barcelona SpainAnatomy Pathology Department Vall d'Hebron Hospital‐UAB Barcelona SpainAnimal Laboratory Unit Biomedical Research Park of Barcelona‐PRBB SpainAnimal Laboratory Unit Biomedical Research Park of Barcelona‐PRBB SpainClinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO) Vall d'Hebron Hospital‐UAB Barcelona SpainDermatology Department Vall d'Hebron Hospital‐UAB Barcelona SpainBiomedical Research in Melanoma‐Animal Models and Cancer Laboratory Vall d'Hebron Research Institute VHIR, Vall d'Hebron Hospital‐UAB Barcelona SpainThe mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1‐depleted mice compared with BrafV600E‐irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1‐null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural‐like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural‐like dedifferentiation.https://doi.org/10.1002/1878-0261.13715BRAFV600ELKB1melanomaneural crest likeultraviolet radiation |
| spellingShingle | Kimberley McGrail Elena González‐Sánchez Paula Granado‐Martínez Roberto Orsenigo Yuxin Ding Berta Ferrer Javier Hernández‐Losa Iván Ortega Juan Martín‐Caballero Eva Muñoz‐Couselo Vicente García‐Patos Juan A. Recio Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation Molecular Oncology BRAFV600E LKB1 melanoma neural crest like ultraviolet radiation |
| title | Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation |
| title_full | Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation |
| title_fullStr | Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation |
| title_full_unstemmed | Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation |
| title_short | Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural‐like dedifferentiation |
| title_sort | loss of lkb1 cooperates with brafv600e and ultraviolet radiation increasing melanoma multiplicity and neural like dedifferentiation |
| topic | BRAFV600E LKB1 melanoma neural crest like ultraviolet radiation |
| url | https://doi.org/10.1002/1878-0261.13715 |
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