Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes
Open accessAbstract
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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MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation.
“MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [25]
The Discussion reports that melanoma cells in a mutant-BRaf mouse model dedifferentiate after an initial phase of expansion, before dermal invasion. But it also says that initial expansion occurred without loss of differentiation markers. The study concerns melanocytes, not epithelial cells, and does not establish that MAPK-driven tumorigenesis generally relies on dedifferentiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGene mutations of BRAF, especially BRAFV600E, and constitutively activated MAPK cascades drive multiple cancers, depriving differentiated features.
“Gene mutations of BRAF, especially BRAFV600E, and constitutively activated MAPK cascades drive multiple types of cancers, depriving differentiated features through melanoma genesis and intestine/colon carcinogenesis24–27.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [25]
The Introduction identifies BRAFV600E-induced melanoma in mice, and the Discussion reports that a subset of melanoma cells later loses its differentiation signature. The Discussion also says the initial expansion retains differentiated features and that what triggers the subsequent dedifferentiation remains unclear. The paper does not establish that MAPK activation causes that loss or address intestinal or colon carcinogenesis. (LLM, conf=0.87)
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References 53 · Cited by 126
Research works printed but not linked: 1
- Hsu, M.Y., Wheelock, M.J., Johnson, K.R., and Herlyn, M. (1996). Shifts in cad- herin profiles between human normal melanocytes and melanomas. J. Investig. Dermatol. Symp. Proc. 1, 188-194.
- Authors
- Köhler, C., Nittner, D., Rambow, F., Radaelli, E., Stanchi, F., Vandamme, N., Baggiolini, A., Sommer, L., Berx, G., van den Oord, J. J., Gerhardt, H., Blanpain, C., & Marine, J.-C.
- Affiliations
- VIB-KU Leuven Center for Cancer Biology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Ghent University (BE)
- University of Zurich (CH)
- Corresponding author
- Marine, Jean-Christophe
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 21
- Issue
- 5
- Pages
- 679-693.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2761074644
- Cited by
- 126
- References
- 53
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 15 · 2023: 13 · 2022: 20 · 2021: 21 · 2020: 18 · 2019: 15 · 2018: 8 · 2017: 3
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Update notices
- erratum (2026-10-13)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Fund for Scientific Research Flanders (G.0664.14)
- Interuniversitaire Attractiepolen (P7/03)
- Stichting tegen Kanker (2014-126)
- Hercules (type 2 research infrastructure grant)
- FWO (11Y9715N, 11Y9717N, 12D3214N)
- European Research Council (consolidator grant 311719 REshape)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- cutaneous melanoma, melanomagenesis, BrafV600E, melanocyte stem cells, melanocyte lineage, tumor cell of origin, clonal expansion, transcriptional reprogramming, tumor microenvironment, melanocyte differentiation, mouse melanoma model, cancer stem cells
- MeSH terms
- Cutaneous Malignant Melanoma, Melanoma, Cutaneous Malignant, Animals, Humans, Melanocytes, Melanoma, Mutation, Neoplasm Invasiveness, Skin Neoplasms, Skin Pigmentation, Tail, Biomarkers, Hair Follicle, Dermis, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice, Cell Dedifferentiation, Stem Cell Niche, Transcriptome, Carcinogenesis
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