A Multistep Immune-Competent Genetically Engineered Mouse Model Reveals Phenotypic Plasticity in Uveal Melanoma.

Uveal melanoma is a highly aggressive intraocular malignancy with limited therapeutic options for metastatic disease. Existing transgenic uveal melanoma mouse models inadequately recapitulate human disease progression, whereas transplant models lack immune competence for studying the tumor immune microenvironment and therapeutic interventions. To address these limitations, we developed a genetically engineered mouse model incorporating stepwise genetic alterations implicated in human uveal melanoma progression. Spatiotemporally controlled expression of mutant GNAQQ209L from the endogenous locus induced choroidal nevi with limited penetrance. Concomitant BAP1 deletion enhanced nevus formation, whereas further MYC activation led to fully penetrant intraocular tumors with the potential to disseminate. Single-cell RNA sequencing revealed that malignant cells segregated into melanocytic and neural crest-like subpopulations characterized by distinct transcriptional and biosynthetic programs. Trajectory analyses inferred dedifferentiation from the melanocytic toward the neural crest-like state during tumor progression. Comparison with human uveal melanoma revealed commonalities with highly aggressive class 2 uveal melanoma, including gene expression signatures and copy-number gains affecting genes that map to human chromosome 8q beyond the activated MYC allele, suggesting cooperative effects of multiple drivers in this chromosomal region. The tumor microenvironment featured immunosuppressive macrophage populations and exhausted T cells, closely resembling human uveal melanoma. This physiologically relevant, immune-competent model provides a platform for investigating uveal melanoma biology, functionally characterizing candidate driver genes, and developing immune-based therapeutic strategies. SIGNIFICANCE: Development of a mouse model resembling the genetic progression and phenotypic plasticity of human uveal melanoma offers an immune-competent preclinical platform for understanding disease immunogenomics and testing immune and targeted treatments.