Molecular Analysis of Murine KitK641E Melanoma Progression

Acral and mucosal melanomas (AMMs) are often driven by mutations in the KIT receptor tyrosine kinase, with nearly 40% harboring alterations in the KIT locus. Despite advances in the knowledge of KIT-mutated melanomas, little is known about the molecular reprogramming that occurs during KIT-mediated melanoma progression due to the rarity of AMMs and the lack of comprehensive biological tools and models. To this end, we used a novel murine model that allows us to ascertain the molecular underpinnings of the stages of cancer progression—transformation, tumorigenesis, immune engagement, and tumor escalation. We found dramatic increases in biosynthetic demands associated with the transformation stage, including DNA and RNA metabolism, leading to replication stress. Tumorigenesis was closely linked to neuronal and axonal development, likely necessary for invasion into the host. Immune engagement highlighted early immune excitation and rejection pathways, possibly triggered by abrupt neoantigen exposure. Finally, tumor escalation pathways proved consistent with immune evasion, with immune-related pathways becoming significantly downregulated. To our knowledge, this is the first time these critical milestones needed for KIT-driven-melanoma tumor formation have been studied at the molecular level using isogenically-matched and phenotypically-defined cells. To investigate Kit mutation induced melanoma transformation, we developed a series of cells lines to model the stages of cancer progression—transformation, tumorigenesis, immune engagement, and tumor escalation. RNAseq analysis of seven lines to obtain gene expression profiles, from which comparative gene expression profiles analysis was conducted.