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

Abstract

Transcriptional reprogramming; Neonatal UV radiation; Melanocytes

Reprogramació transcripcional; Radiació UV neonatal; Melanòcits

Reprogramación transcripcional; Radiación UV neonatal; Melanocitos

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.

This work was funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “A way to make Europe”/“Investing in your future”), PI17/00043-Fondos FEDER; PI20/0384-Fondos FEDER; PI23/00428-Fondos FEDER JAR, Euronanomed2-ISCIII (AC16/00019)-Fondos FEDER; JAR, Asociación Española Contra el Cancer (AECC-GCB15152978SOEN). AGAUR, 2021-SGR00653 JAR (supported PGM, KM); Ramón Areces Foundation (supported KM and research); JAR. We thank Joan Seoane, HG Palmer, and FM Barriga for their critical comments.