Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes

Cell Stem Cell. 2017 Nov 2;21(5):679-693.e6. doi: 10.1016/j.stem.2017.08.003. Epub 2017 Oct 12.

Abstract

To identify the cells at the origin of melanoma, we combined single-cell lineage-tracing and transcriptomics approaches with time-lapse imaging. A mouse model that recapitulates key histopathological features of human melanomagenesis was created by inducing a BRafV600E-driven melanomagenic program in tail interfollicular melanocytes. Most targeted mature, melanin-producing melanocytes expanded clonally within the epidermis before losing their differentiated features through transcriptional reprogramming and eventually invading the dermis. Tumors did not form within interscales, which contain both mature and dormant amelanotic melanocytes. The hair follicle bulge, which contains melanocyte stem cells, was also refractory to melanomagenesis. These studies identify varying tumor susceptibilities within the melanocytic lineage, highlighting pigment-producing cells as the melanoma cell of origin, and indicate that regional variation in tumor predisposition is dictated by microenvironmental cues rather than intrinsic differences in cellular origin. Critically, this work provides in vivo evidence that differentiated somatic cells can be reprogrammed into cancer initiating cells.

Keywords: cell of origin; cutaneous melanoma; lineage tracing; mouse model; single-cell transcriptomics; time-lapse imaging.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Dedifferentiation*
  • Cell Proliferation
  • Dermis / pathology
  • Hair Follicle / pathology
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology*
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice
  • Mutation / genetics*
  • Neoplasm Invasiveness
  • Proto-Oncogene Proteins B-raf / genetics*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Skin Pigmentation*
  • Stem Cell Niche
  • Tail
  • Transcriptome / genetics

Substances

  • Biomarkers
  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Melanoma, Cutaneous Malignant