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

Qi Sun, Wendy Lee, Yasuaki Mohri, Makoto Takeo, Chae Ho Lim, Xiaowei Xu, Peggy Myung, Radhika P. Atit, M. Mark Taketo, Rana S. Moubarak, Markus Schober, Iman Osman, Denise L. Gay, Dieter Saur, Emi K. Nishimura and Mayumi Ito ()
Additional contact information
Qi Sun: New York University, School of Medicine
Wendy Lee: New York University, School of Medicine
Yasuaki Mohri: Tokyo Medical and Dental University
Makoto Takeo: New York University, School of Medicine
Chae Ho Lim: New York University, School of Medicine
Xiaowei Xu: Hospital of the University of Pennsylvania
Peggy Myung: Yale Cancer Center, Yale School of Medicine
Radhika P. Atit: Case Western Reserve University
M. Mark Taketo: Kyoto University
Rana S. Moubarak: New York University, School of Medicine
Markus Schober: New York University, School of Medicine
Iman Osman: New York University, School of Medicine
Denise L. Gay: Inserm UMR_967, CEA/DRF/IBFJ/iRCM/LRTS
Dieter Saur: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Emi K. Nishimura: Tokyo Medical and Dental University
Mayumi Ito: New York University, School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12733-1

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