Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
Department of Medicine, Division of Dermatology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Stem Cell. 2017 Nov 2;21(5):665-678.e6. doi: 10.1016/j.stem.2017.09.001. Epub 2017 Oct 12.
Melanoma is one of the deadliest cancers, yet the cells of origin and mechanisms of tumor initiation remain unclear. The majority of melanomas emerge from clear skin without a precursor lesion, but it is unknown whether these melanomas can arise from melanocyte stem cells (MCSCs). Here we employ mouse models to define the role of MCSCs as melanoma cells of origin, demonstrate that MCSC quiescence acts as a tumor suppressor, and identify the extrinsic environmental and molecular factors required for the critical early steps of melanoma initiation. Specifically, melanomas originate from melanoma-competent MCSCs upon stimulation by UVB, which induces MCSC activation and translocation via an inflammation-dependent process. Moreover, the chromatin-remodeling factor Hmga2 in the skin plays a critical role in UVB-mediated melanomagenesis. These findings delineate melanoma formation from melanoma-competent MCSCs following extrinsic stimuli, and they suggest that abrogation of Hmga2 function in the microenvironment can suppress MCSC-originating cutaneous melanomas.
黑色素瘤是最致命的癌症之一，但起源细胞和肿瘤起始机制仍不清楚。大多数黑色素瘤起源于无前期病变的透明皮肤，但尚不清楚这些黑色素瘤是否可以起源于黑素细胞干细胞（MCSC）。在这里，我们利用小鼠模型来确定 MCSC 作为黑色素瘤起源细胞的作用，证明 MCSC 静止作为一种肿瘤抑制物，并确定黑色素瘤起始的关键早期步骤所需的外在环境和分子因素。具体来说，黑色素瘤起源于受 UVB 刺激的具有黑色素瘤能力的 MCSC，UVB 通过炎症依赖性过程诱导 MCSC 激活和易位。此外，皮肤中的染色质重塑因子 Hmga2 在 UVB 介导的黑色素瘤发生中起着关键作用。这些发现描述了黑色素瘤从具有黑色素瘤能力的 MCSC 在外在刺激下形成，并表明微环境中 Hmga2 功能的缺失可以抑制源自 MCSC 的皮肤黑色素瘤。
