Loss ofLkb1cooperates withBrafV600Eand UV radiation increasing melanoma multiplicity and neural-like dedifferentiation

Abstract

ABSTRACTThe mechanisms cooperating withBRAFV600Eoncogene in addition to ultraviolet (UV) radiation in melanoma development are of great interest. Analysis of human melanoma tumors (TCGA) indicates that 50% or more of the samples express no or low amounts of LKB1 protein. Here, we report that the concomitant neonatalBrafV600Eactivation andLkb1tumor suppressor ablation in melanocytes led to full melanoma development. A postnatal single-dose of UVB radiation had no effect on melanoma onset inLkb1-depleted mice in respect toBrafV600E-irradiated mice, but increased tumor multiplicity. In agreement to this and previous reports,Lkb1null irradiated mice showed a deficient DNA damage repair (DDR). Histologically, tumors lackingLkb1were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor samples-mutated genes indicated that loss ofLkb1promoted the selection of altered genes associated to neural differentiation processes. Thus, these results suggest that loss ofLkb1cooperates withBrafV600Eand UVR impairing DDR and increasing melanoma multiplicity and neural-like dedifferentiation.