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

McGrail, K. A.; Gonzlez-Sanchez, E.; Granado-Martinez, P.; Orsenigo, R.; Ding, Y.; Ferrer, B.; Hernandez-Losa, J.; Ortega, I.; Martin-Caballero, J.; Munoz-Couselo, E.; Garcia-Patos, V.; Recio, J. A.

doi:10.1101/2024.03.29.587140

bioRxiv · 10.1101/2024.03.29.587140

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

McGrail, K. A.·Gonzlez-Sanchez, E.·Granado-Martinez, P.·Orsenigo, R.·Ding, Y.·Ferrer, B.·Hernandez-Losa, J.·Ortega, I.·Martin-Caballero, J.·Munoz-Couselo, E.·Garcia-Patos, V.·Recio, J. A.

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Abstract

The mechanisms cooperating with BRAFV600E 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 BrafV600E 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 BrafV600E-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 BrafV600E and UVR impairing DDR and increasing melanoma multiplicity and neural-like dedifferentiation.

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McGrail, K. A., Gonzlez-Sanchez, E., Granado-Martinez, P., Orsenigo, R., Ding, Y., Ferrer, B., Hernandez-Losa, J., Ortega, I., Martin-Caballero, J., Munoz-Couselo, E., Garcia-Patos, V., Recio, J. A.. 2024-03-29. Loss of Lkb1 cooperates with BrafV600E and UV radiation increasing melanoma multiplicity and neural-like dedifferentiation. https://doi.org/10.1101/2024.03.29.587140

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