Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural-like dedifferentiation

Abstract

Melanoma; Neural crest like; Ultraviolet radiation

Melanoma; Cresta neural; Radiación ultravioleta

Melanoma; Cresta neural; Radiació ultraviolada

The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with BrafV600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited 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 sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.

This work was funded by Instituto de Salud Carlos III and co-funded by the 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, Institute of Health Carlos III-Euronanomed-II (AC16/00019)-Fondos FEDER European Union; and JAR, Asociación Española Contra el Cancer (AECC-GCB15152978SOEN). AGAUR, 2021-SGR00653 JAR (supported PG-M, KM); Ramón Areces Foundation (supported KM and research); JAR.