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

Abstract

The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAF^V600E 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 BRAF^V600E-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 BRAF^V600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAF^V600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.