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Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2017-Nov-02 , DOI: 10.1016/j.stem.2017.08.003 Corinna Köhler 1 , David Nittner 1 , Florian Rambow 1 , Enrico Radaelli 2 , Fabio Stanchi 3 , Niels Vandamme 4 , Arianna Baggiolini 5 , Lukas Sommer 5 , Geert Berx 4 , Joost J van den Oord 6 , Holger Gerhardt 3 , Cedric Blanpain 7 , Jean-Christophe Marine 1
Cell Stem Cell ( IF 19.8 ) Pub Date : 2017-Nov-02 , DOI: 10.1016/j.stem.2017.08.003 Corinna Köhler 1 , David Nittner 1 , Florian Rambow 1 , Enrico Radaelli 2 , Fabio Stanchi 3 , Niels Vandamme 4 , Arianna Baggiolini 5 , Lukas Sommer 5 , Geert Berx 4 , Joost J van den Oord 6 , Holger Gerhardt 3 , Cedric Blanpain 7 , Jean-Christophe Marine 1
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To identify the cells at the origin of melanoma, we combined single-cell lineage-tracing and transcriptomics approaches with time-lapse imaging. A mouse model that recapitulates key histopathological features of human melanomagenesis was created by inducing a BRafV600E-driven melanomagenic program in tail interfollicular melanocytes. Most targeted mature, melanin-producing melanocytes expanded clonally within the epidermis before losing their differentiated features through transcriptional reprogramming and eventually invading the dermis. Tumors did not form within interscales, which contain both mature and dormant amelanotic melanocytes. The hair follicle bulge, which contains melanocyte stem cells, was also refractory to melanomagenesis. These studies identify varying tumor susceptibilities within the melanocytic lineage, highlighting pigment-producing cells as the melanoma cell of origin, and indicate that regional variation in tumor predisposition is dictated by microenvironmental cues rather than intrinsic differences in cellular origin. Critically, this work provides in vivo evidence that differentiated somatic cells can be reprogrammed into cancer initiating cells.
中文翻译：
突变 BRaf 诱发的小鼠皮肤黑色素瘤是由成熟色素黑色素细胞的扩张和去分化引起的。
为了识别黑色素瘤起源的细胞，我们将单细胞谱系追踪和转录组学方法与延时成像相结合。通过在尾部滤泡间黑色素细胞中诱导 BRafV600E 驱动的黑色素瘤生成程序，创建了重现人类黑色素瘤生成的关键组织病理学特征的小鼠模型。大多数目标成熟、产生黑色素的黑素细胞在表皮内克隆扩增，然后通过转录重编程失去其分化特征并最终侵入真皮。肿瘤不在鳞间形成，鳞间含有成熟和休眠的无黑素细胞。毛囊隆起含有黑色素细胞干细胞，也难以形成黑色素瘤。这些研究确定了黑素细胞谱系内不同的肿瘤易感性，强调产生色素的细胞是黑色素瘤细胞的起源，并表明肿瘤易感性的区域差异是由微环境线索决定的，而不是细胞起源的内在差异。重要的是，这项工作提供了体内证据，证明分化的体细胞可以被重新编程为癌症起始细胞。
更新日期：2017-10-12
中文翻译：
突变 BRaf 诱发的小鼠皮肤黑色素瘤是由成熟色素黑色素细胞的扩张和去分化引起的。
为了识别黑色素瘤起源的细胞，我们将单细胞谱系追踪和转录组学方法与延时成像相结合。通过在尾部滤泡间黑色素细胞中诱导 BRafV600E 驱动的黑色素瘤生成程序，创建了重现人类黑色素瘤生成的关键组织病理学特征的小鼠模型。大多数目标成熟、产生黑色素的黑素细胞在表皮内克隆扩增，然后通过转录重编程失去其分化特征并最终侵入真皮。肿瘤不在鳞间形成，鳞间含有成熟和休眠的无黑素细胞。毛囊隆起含有黑色素细胞干细胞，也难以形成黑色素瘤。这些研究确定了黑素细胞谱系内不同的肿瘤易感性，强调产生色素的细胞是黑色素瘤细胞的起源，并表明肿瘤易感性的区域差异是由微环境线索决定的，而不是细胞起源的内在差异。重要的是，这项工作提供了体内证据，证明分化的体细胞可以被重新编程为癌症起始细胞。
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