Recent Advances in Genetically Engineered Mouse Models of Melanoma: Insights into Tumor Initiation and Oncogenic Signaling Pathways

Genetically engineered mouse (GEM) models are essential for elucidating the cellular and molecular mechanisms underlying various human diseases. Because mouse skin closely resembles the structure and lineage organization of human skin, melanoma GEM models enable the investigation of melanoma initiation in melanocytes and melanocyte stem cells, along with its progression from the epidermis to the dermis. Although early melanoma development is mainly regulated by major oncogenic signaling pathways, including MAPK and PI3K, recent studies have uncovered additional regulatory pathways, including Cdk4-mediated cell-cycle control, Jak-Stat-mediated transcriptional regulation, Hippo-Yap/Taz signaling, the p62-Igf2bp1 axis, and epigenetic regulators such as Tet2, which contribute to melanoma heterogeneity and phenotypic plasticity. This review summarizes the recent advances in melanoma GEM models, highlights the oncogenic signaling pathways active in these systems, and discusses the molecular insights derived from these models regarding melanoma initiation, progression, and intratumoral diversity. These findings highlight the utility of GEM models for elucidating melanoma biology and identifying potential therapeutic targets.