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

Qi Sun,Yasuaki Mohri,Emi K Nishimura,M Mark Taketo,Rana S Moubarak,Denise L Gay,Xiaowei Xu,Dieter Saur,Markus Schober,Chae Ho Lim,Mayumi Ito,Wendy Lee,Peggy Myung,Radhika P Atit,Iman Osman,Makoto Takeo

doi:10.1038/s41467-019-12733-1

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.

Highlights

Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages
To test the ability of the c-Kit promoter to target melanocyte stem cells (McSCs) from the hair follicles away from the dermal melanocytes in the skin, we generated c-KitCreER; R26R-mTmG (c-Kit-CreER: R26R-GFP) mice in which membrane-bound GFP is expressed by c-Kit+ cells and their progeny following tamoxifen (TAM) treatment26. 7-week old mice were injected with TAM for 3 days, during a period when hair follicles in the back skin are in telogen phase and only harbor McSCs27,28 (Fig. 1a)
McSCs are defined as dopachrome tautomerase (Dct)+ cells in the bulge/secondary hair germ of the telogen hair follicle[27,28]

Summary

Introduction

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. The current model of human melanoma progression proposes that melanomas first arise in skin epidermis during the radial growth phase, and invade into the dermis for continued expansion during the vertical growth phase[1] In this latter phase, melanoma cells can establish a heterogeneous tumor composed of subpopulations with distinct proliferative, biochemical and metastatic signatures[2]. Because Tyr-CreER can target both McSCs located in the hair follicle and melanocytes (Mcs) in the dermis[8,9] and melanoma forms primarily in the dermis of these mice[7], it has proven difficult to conclusively establish the origin of melanoma using this model Another melanoma mouse model, constitutively expressing hepatocyte growth factor/scatter factor (HGF/SF) for the migration of melanocytes to the epidermis, develops melanoma at the dermo-epidermal junction upon ultraviolet (UV) irradiation[10,11,12,13]. Potential regenerative niche signals that synergize with oncogenic mutations to promote the transformation of normal melanocytes into melanoma remain unknown

Methods

Results

Conclusion