Loss of Lkb1 cooperates with Braf ^V600E and UV radiation increasing melanoma multiplicity and neural-like dedifferentiation

The mechanisms cooperating with BRAF ^V600E oncogene 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 neonatal Braf ^V600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A postnatal single-dose of UVB radiation had no effect on melanoma onset in Lkb1 -depleted mice in respect to Braf ^V600E -irradiated mice, but increased tumor multiplicity. In agreement to this and previous reports, Lkb1 null irradiated mice showed a deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor samples-mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated to neural differentiation processes. Thus, these results suggest that loss of Lkb1 cooperates with Braf ^V600E and UVR impairing DDR and increasing melanoma multiplicity and neural-like dedifferentiation.