Stem cell spreading dynamics intrinsically differentiate acral melanomas from nevi.

Sally Eshiba,Hiroo Yokozeki,Tomomi Aida,Takeshi Namiki,Masaru Tanaka,Yasuaki Mohri,Kohichi Tanaka,Takakazu Shibata,Keiko Miura,Hironobu Morinaga,Hisashi Uhara,Daisuke Nanba,Naotaka Serizawa,Toshiaki Saida,Emi K Nishimura,Yuichi Hiraoka

doi:10.1016/j.celrep.2021.109492

Abstract

Early differential diagnosis between malignant and benign tumors and their underlying intrinsic differences are the most critical issues for life-threatening cancers. To study whether human acral melanomas, deadly cancers that occur on non-hair-bearing skin, have distinct origins that underlie their invasive capability, we develop fate-tracing technologies of melanocyte stem cells in sweat glands (glandular McSCs) and in melanoma models in mice and compare the cellular dynamics with human melanoma. Herein, we report that glandular McSCs self-renew to expand their migratory progeny in response to genotoxic stress and trauma to generate invasive melanomas in mice that mimic human acral melanomas. The analysis of melanocytic lesions in human volar skin reveals that genetically unstable McSCs expand in sweat glands and in the surrounding epidermis in melanomas but not in nevi. The detection of such cell spreading dynamics provides an innovative method for an early differential diagnosis of acral melanomas from nevi.

Highlights

Tumor invasiveness most reliably distinguishes malignant from benign tumors (Weinberg, 2014), yet the exact underlying mechanisms that distinguish the initial tumor fates are still largely unknown
Ultraviolet radiation (UVR) induces sweat gland-centric skin pigmentation in human volar skin Human vitiligo is characterized by patchy depigmented lesions caused by the disappearance of epidermal melanocytes (Roberts et al, 2020)
Pigmented melanocytes appeared transiently at ridge areas with an eccrine duct-centric distribution pattern (Figures 1B and 1I–1K), which may suggest that non-epidermal reservoirs of skin pigmentation or glandular Melanocyte stem cells (McSCs) in acral volar skin serve as a potential origin of acral melanoma

Summary

Introduction

Tumor invasiveness most reliably distinguishes malignant from benign tumors (Weinberg, 2014), yet the exact underlying mechanisms that distinguish the initial tumor fates are still largely unknown. Most benign tumors are stably cell cycle arrested and rarely develop into metastatic tumors even with aging (Kuilman et al, 2010). A malignancy of the melanocytic lineage, is the most aggressive and deadly skin cancer because of its highly invasive and metastatic characteristics. Benign nevi are generally characterized by the formation of nests containing cell cycle-arrested melanocytic cells (nevocytes) after their limited local expansion (Dhomen et al, 2009; Ross et al, 2011).

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