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

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

Author information

1
Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, 3000 Leuven, Belgium.
2
Mouse Histopathology Core Facility, VIB Center for Brain Disease, VIB, 3000 Leuven, Belgium; Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051, USA.
3
Vascular Patterning Laboratory, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium.
4
Molecular and Cellular Oncology Laboratory, Cancer Research Institute Ghent (CRIG), 9052 Ghent University, Ghent, Belgium.
5
Stem Cell Biology, Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland.
6
Laboratory of Translational Cell and Tissue Research, Department of Pathology, KULeuven and UZ Leuven, 3000 Leuven, Belgium.
7
Laboratory of Stem Cells and Cancer, Welbio, Université Libre de Bruxelles, 1070 Bruxelles, Belgium.
8
Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, 3000 Leuven, Belgium. Electronic address: jeanchristophe.marine@vib.kuleuven.be.

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

PMID:
29033351
DOI:
10.1016/j.stem.2017.08.003
[Indexed for MEDLINE]
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