Comparison of Human Melanoma Single Cell Profiles to Evolutionary Medicine Model Xiphophorus Provides Insights in Disease Control.

Melanoma remains one of the deadliest forms of cancer. Despite recent therapeutic advances, including immune checkpoint inhibitors and small-molecule kinase inhibitors, patients frequently develop treatment resistance. Novel models are needed to devise strategies that overcome resistance and further reduce melanoma-related mortality. Interspecies hybrid fish from the Xiphophorus lineage develop mutant Epidermal Growth Factor Receptor (EGFR)-driven melanomas that display morphology, bulk gene expression, disease initiation, and progression processes mimicking those of human melanomas. These similarities have enabled their comparative use in evaluating why human melanomas exhibit cancer cell plasticity and how the cancer cells interact with diverse immune populations. However, it remains unclear whether Xiphophorus melanomas recapitulate some or all these features. To address this, we performed single-nucleus RNA sequencing (snRNAseq) analysis of Xiphophorus melanomas. Employing comparative analyses with results from human melanoma studies, we demonstrate that Xiphophorus melanomas faithfully mimic the cellular heterogeneity observed in human melanoma, including cancer cells, endothelial cells, cancer-associated fibroblasts, B cells, M1 and M2 macrophages, N1 and N2 neutrophils, various T helper cells, and less cytotoxic, but not exhausted CD8+ T cells. Immune and cancer cell subtyping showed Xiphophorus melanoma represented an immune-evaded status.