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

Publication date: Available online 12 October 2017
Source:Cell Stem Cell
Author(s): Corinna Köhler, David Nittner, Florian Rambow, Enrico Radaelli, Fabio Stanchi, Niels Vandamme, Arianna Baggiolini, Lukas Sommer, Geert Berx, Joost J. van den Oord, Holger Gerhardt, Cedric Blanpain, Jean-Christophe Marine
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.

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Teaser

The precise cellular origin of cutaneous melanoma has been a topic of intense debate. Using a refined mouse model that faithfully recapitulates key histopathological features of early stages of human melanomagenesis, Köhler et al. report that melanoma can arise from mature, pigment-producing melanocytes located within the interfollicular epidermis.


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