美国约翰霍普金斯大学Ashani T. Weeraratna研究组揭示衰老肺基质改变导致黑色素瘤休眠。2022年6月1日，国际知名学术期刊《自然》发表了这一成果。
他们展示了衰老肺微环境促进了一个允许休眠的播散癌细胞有效生长的生态位 - 与衰老的皮肤相反，其中与衰老相关的变化抑制黑色素瘤的生长但驱动扩散。这些微环境的复杂性可以通过表型转换模型来解释，该模型认为黑色素瘤细胞在增殖细胞状态和较慢循环的侵袭性状态之间转换。先前的研究表明，真皮成纤维细胞在衰老过程中促进黑色素瘤的表型转换。
他们现在将 WNT5A 鉴定为肺内黑色素瘤播散性癌细胞休眠的激活剂，这最初使黑色素瘤细胞能够在转移性生态位中有效扩散和定植。衰老诱导的肺成纤维细胞重编程增加了可溶性 WNT 拮抗剂 sFRP1 的分泌，该拮抗剂抑制黑色素瘤细胞中的 WNT5A，从而实现有效的转移性生长。他们还确定酪氨酸激酶受体 AXL 和 MER 促进黑色素瘤细胞内的休眠-再激活轴。总体而言，他们发现远端转移微环境中由衰老引起的变化促进了肺中休眠黑色素瘤细胞的有效再激活。
据介绍，来自原发性肿瘤的扩散性癌细胞可以在远端组织中定植，但可能需要几年时间才能形成明显的转移，这种现象被称为肿瘤休眠。尽管它在转移和残留疾病中很重要，但很少有研究能够成功地表征黑色素瘤内的休眠。
附：英文原文
Title: Stromal changes in the aged lung induce an emergence from melanoma dormancy
Author: Fane, Mitchell E., Chhabra, Yash, Alicea, Gretchen M., Maranto, Devon A., Douglass, Stephen M., Webster, Marie R., Rebecca, Vito W., Marino, Gloria E., Almeida, Filipe, Ecker, Brett L., Zabransky, Daniel J., Hser, Laura, Beer, Thomas, Tang, Hsin-Yao, Kossenkov, Andrew, Herlyn, Meenhard, Speicher, David W., Xu, Wei, Xu, Xiaowei, Jaffee, Elizabeth M., Aguirre-Ghiso, Julio A., Weeraratna, Ashani T.
Issue&Volume: 2022-06-01
Abstract: Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1,2,3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4,5,6,7,8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
DOI: 10.1038/s41586-022-04774-2
Source: https://www.nature.com/articles/s41586-022-04774-2
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
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
