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

Area of Science:

• Ophthalmology
• Oncology
• Genetics

Background:

• Uveal melanoma (UM) is an aggressive eye cancer with few treatment options for metastasis.
• Current mouse models fail to fully replicate human UM, limiting research into its tumor microenvironment and potential therapies.

Purpose of the Study:

• To develop a genetically engineered, immune-competent mouse model that accurately recapitulates human uveal melanoma (UM) progression and its associated tumor microenvironment.
• To provide a platform for investigating UM pathogenesis and evaluating novel therapeutic strategies, particularly immune-based interventions.

Main Methods:

• Developed a genetically engineered mouse model with stepwise genetic alterations (GNAQ, BAP1, MYC) mimicking human UM drivers.
• Utilized single-cell RNA sequencing and trajectory analyses to characterize tumor cell subpopulations and progression.
• Analyzed the tumor microenvironment, including immune cell populations, in the developed model.

Main Results:

• The model successfully generated uveal melanoma with metastatic potential, closely resembling human Class 2 UM.
• Identified distinct melanocytic and neural crest-like malignant cell subpopulations with inferred dedifferentiation during progression.
• Observed an immunosuppressive tumor microenvironment with macrophages and exhausted T cells, mirroring human UM.
• Detected copy number gains on chromosome 8q, suggesting cooperative driver effects.

Conclusions:

• The developed mouse model is a physiologically relevant and immune-competent platform for studying uveal melanoma.
• This model facilitates functional characterization of UM driver genes and the development of effective immune-based therapies for metastatic disease.