2. Academic Validation
  3. Transcriptional reprogramming triggered by neonatal UV radiation or Lkb1 loss prevents BRAFV600E-induced growth arrest in melanocytes

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

  • Oncogene. 2025 Jun;44(21):1592-1608. doi: 10.1038/s41388-025-03339-7.
Kimberley McGrail 1,  Paula Granado-Martínez 1,  Roberto Orsenigo 1,  Ginevra Caratù 2,  Paula Nieto 2,  Holger Heyn 2,  Berta Ferrer 3,  Javier Hernández-Losa 3,  Eva Muñoz-Couselo 4,  Vicenç García-Patos 5,  Juan A Recio 6
Affiliations

Affiliations

  • 1 Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  • 2 Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain.
  • 3 Anatomy Pathology Department, Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  • 4 Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  • 5 Dermatology Department, Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  • 6 Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain. [email protected].
PMID: 40057604 DOI: 10.1038/s41388-025-03339-7
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.

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