A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease

• Published in: Nature communications 2019-11, Vol.10 (1), p.5023-16, Article 5023
• Main Authors: Sun, Qi, Lee, Wendy, Mohri, Yasuaki, Takeo, Makoto, Lim, Chae Ho, Xu, Xiaowei, Myung, Peggy, Atit, Radhika P., Taketo, M. Mark, Moubarak, Rana S., Schober, Markus, Osman, Iman, Gay, Denise L., Saur, Dieter, Nishimura, Emi K., Ito, Mayumi
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/31; 13/51; 14/63; 38/91; 631/532/2438; 631/67/1813/1634; 631/67/2329; 631/67/70; 64/110; 64/60; Animal models; Animals; c-Kit protein; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Transformation, Neoplastic - pathology; Dermis; Dermis - pathology; Disease Models, Animal; Endothelins; Epidermis - pathology; Genetic transformation; Heterogeneity; Homeostasis; Humanities and Social Sciences; Humans; Melanocytes - metabolism; Melanocytes - pathology; Melanoma; Melanoma - pathology; Mice; multidisciplinary; Mutation - genetics; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotype; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-kit - metabolism; Science; Science (multidisciplinary); Skin cancer; Skin diseases; Stem cell transplantation; Stem cells; Tumor Microenvironment; Wnt protein; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12733-1

Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER -driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma. Currently, few mouse models exist to recapitulate human melanomagenesis. Here, the authors establish a c-Kit-CreER-driven model to target melanocyte stem cells (McSCs) and show that oncogenic McSCs give rise to epidermal melanoma that invade into the dermis, similar to human melanoma.