MLKL deficiency in Braf(V600E)Pten(−/−) melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice

Cancers acquire several capabilities to survive the multistep process in carcinogenesis. Resisting cell death is one of them. Silencing of the necroptosis initiator Ripk3 occurs in a wide variety of cancer types including melanoma. Little is known about the role of the necroptosis executioner MLKL in tumor development. Studies often indicate opposing roles for MLKL as a tumor-suppressing or a tumor-promoting protein. This study investigates the role of MLKL during melanoma initiation and progression using a tamoxifen-inducible melanoma mouse model driven by melanocyte-specific overexpression of mutated Braf and simultaneous deletion of Pten (Braf(V600E)Pten(−/−)). In this model we observed a clear sex difference: melanoma initiation and progression were faster in females mice. Mlkl deficiency in male mice resulted in a modest but significant reduction of nevi growth rate compared to the littermate control. In these mice, infiltration and expansion of melanoma cells in the inguinal lymph node were also modestly decreased. This is likely to be a consequence of the delay in nevi development. No significant difference was observed in the Mlkl-deficient condition in female mice in which melanoma development was faster. Overall, our results indicate that in this genetic model MLKL has a minor role during melanoma initiation and progression.