Uncovering Minimal Pathways in Melanoma Initiation

Melanomas are genetically heterogeneous, displaying MAP kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing, pigmented tumors. In contrast, rare, slow-growing, lowly-pigmented tumors arise in mice combining Braf activation with heterozygous loss of Pten or, as we show here, in albino mice bearing only a Braf mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis, but responsible de novo mutations or structural variants were not found. Single-cell transcriptomics of tumors identified a cell type resembling "neural crest-like" cells in human and mouse melanomas. These exist in normal mouse skin, expand upon Braf activation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that, while not abundant in fast-growing, heavily-mutated tumors, may provide a diagnostically and therapeutically important source of cellular heterogeneity. Overview design: tumor, skin, and spleen samples were collected from Albino Braf-mutant mice (n=3) and subjected to Whole genome sequencing (WGS), using the NEXTflex Rapid DNA-Seq kit v2 on the NovaSeq 6000 Sequencer.