小柯机器人

美国纪念斯隆凯特琳癌症中心Richard M. White及其团队发现解剖部位决定了黑色素瘤的致癌特异性。该研究于2022年3月30日发表于国际学术期刊《自然》杂志。

研究人员发现解剖位置是细胞对特定癌基因有反应的主要决定因素。皮肤黑色素瘤出现在全身，而肢端亚型出现在手掌、脚底或指甲下。通过对许多患者的皮肤和肢端黑色素瘤细胞进行DNA测序，研究人员发现了皮肤黑色素瘤中存在BRAF突变的特异性富集和肢端黑色素瘤中CRKL扩增的富集。研究人员在转基因斑马鱼模型中模拟了这些变化，发现CRKL诱导的肿瘤主要发生在鱼鳍中。鳍是四肢动物肢体的进化前体，表明这些肢端位置的黑素细胞可能对CRKL具有独特的敏感性。

与身体黑素细胞相比，对鳍和四肢黑素细胞的RNA分析揭示了以HOX13基因为代表的位置同一性基因程序。这种定位基因程序与CRKL协同作用放大了胰岛素样生长因子(IGF)信号并诱导肢端部位肿瘤的产生。CRKL驱动程序的缺失消除了肢端黑色素瘤的解剖学特异性。这些数据表明，祖细胞的解剖位置赋予其独特的转录状态，使其仅对某些致癌损伤敏感。

据介绍，DNA的致癌改变并非发生在所有细胞环境中。这可能是由于祖细胞中预先存在某些转录程序。

附：英文原文

Title: Anatomic position determines oncogenic specificity in melanoma

Author: Weiss, Joshua M., Hunter, Miranda V., Cruz, Nelly M., Baggiolini, Arianna, Tagore, Mohita, Ma, Yilun, Misale, Sandra, Marasco, Michelangelo, Simon-Vermot, Theresa, Campbell, Nathaniel R., Newell, Felicity, Wilmott, James S., Johansson, Peter A., Thompson, John F., Long, Georgina V., Pearson, John V., Mann, Graham J., Scolyer, Richard A., Waddell, Nicola, Montal, Emily D., Huang, Ting-Hsiang, Jonsson, Philip, Donoghue, Mark T. A., Harris, Christopher C., Taylor, Barry S., Xu, Tianhao, Chalign, Ronan, Shliaha, Pavel V., Hendrickson, Ronald, Jungbluth, Achim A., Lezcano, Cecilia, Koche, Richard, Studer, Lorenz, Ariyan, Charlotte E., Solit, David B., Wolchok, Jedd D., Merghoub, Taha, Rosen, Neal, Hayward, Nicholas K., White, Richard M.

Issue&Volume: 2022-03-30

Abstract: Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

DOI: 10.1038/s41586-022-04584-6

Source: https://www.nature.com/articles/s41586-022-04584-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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