Uncovering minimal pathways in melanoma initiation

Melanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combining Braf activation with heterozygous loss of Pten. Here we show that similar tumors can arise in albino mice bearing only a Braf mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only a Braf mutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify 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 may provide a diagnostically and therapeutically important source of cellular heterogeneity.