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Transcriptional reprogramming triggered by neonatal UV radiation or Lkb1 loss prevents BRAFV600E-induced growth arrest in melanocytes

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Titel: Transcriptional reprogramming triggered by neonatal UV radiation or Lkb1 loss prevents BRAFV600E-induced growth arrest in melanocytes
Autoren: Kimberley McGrail, Paula Granado-Martínez, Roberto Orsenigo, Ginevra Caratù, Paula Nieto, Holger Heyn, Berta Ferrer, Javier Hernández-Losa, Eva Muñoz-Couselo, Vicenç García-Patos, Juan A. Recio
Weitere Verfasser: Institut Català de la Salut, [McGrail K, Granado-Martínez P, Orsenigo R, Recio JA] Grup de Recerca Biomèdica en Melanoma, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Caratù G, Nieto P, Heyn H] Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain. [Ferrer B, Hernández-Losa J] Servei d’Anatomia Patològica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Muñoz-Couselo E] Clinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [García-Patos V] Servei de Dermatologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
Quelle: Oncogene
Scientia
Scientia. Dipòsit d'Informació Digital del Departament de Salut
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Verlagsinformationen: Springer Science and Business Media LLC, 2025.
Publikationsjahr: 2025
Schlagwörter: Proto-Oncogene Proteins B-raf, Skin Neoplasms, Ultraviolet Rays, PHENOMENA AND PROCESSES::Physical Phenomena::Magnetic Phenomena::Electromagnetic Phenomena::Electromagnetic Radiation::Light::Ultraviolet Rays, Protein Serine-Threonine Kinases, AMP-Activated Protein Kinases, Article, DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neuroendocrine Tumors::Melanoma, ANATOMÍA::células::células epidérmicas::melanocitos, Pell - Càncer - Aspectes genètics, Mice, AMP-Activated Protein Kinase Kinases, Melanoma - Aspectes genètics, Animals, Humans, FENÓMENOS Y PROCESOS::fenómenos genéticos::reprogramación celular, Melanoma, Rates (Animals de laboratori), PHENOMENA AND PROCESSES::Genetic Phenomena::Cellular Reprogramming, Radiació ultraviolada, ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::tumores neuroendocrinos::melanoma, ANATOMY::Cells::Epidermal Cells::Melanocytes, Cellular Reprogramming, Gene Expression Regulation, Neoplastic, Animals, Newborn, FENÓMENOS Y PROCESOS::fenómenos físicos::fenómenos magnéticos::fenómenos electromagnéticos::radiación electromagnética::luz::rayos ultravioleta, Mutation, Melanocytes, ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias cutáneas, DISEASES::Neoplasms::Neoplasms by Site::Skin Neoplasms, ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Mice, ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas
Beschreibung: The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAFV600E are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAFV600E-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAFV600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAFV600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.
Publikationsart: Article
Other literature type
Dateibeschreibung: application/pdf
Sprache: English
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-025-03339-7
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/40057604
http://hdl.handle.net/11351/13356
Rights: CC BY NC ND
Dokumentencode: edsair.doi.dedup.....692d5f8b98e86d42df31323f4b8ab211
Datenbank: OpenAIRE
Beschreibung
Abstract:The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAFV600E are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAFV600E-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAFV600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAFV600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.
ISSN:14765594
09509232
DOI:10.1038/s41388-025-03339-7