桥粒体突变通过影响肿瘤微环境促进黑色素瘤增殖，这一成果由加州大学Ideker, Trey研究组经过不懈努力而取得。相关论文发表在2025年4月16日出版的《自然—遗传学》杂志上。

该研究团队报告在人类癌症中发现频繁的桥粒基因改变，其中最强烈的信号出现在皮肤黑色素瘤中，超过70%的病例中桥粒发生突变。在原发性而非转移性黑色素瘤活检中，桥粒基因编码突变的负担与桥粒基因表达的强烈减少有关。空间转录组学和蛋白质免疫荧光分析表明，微环境中的角化细胞而不是原发性黑色素瘤细胞中表达减少。为了进一步支持微环境起源，该团队发现在角质形成细胞和黑色素瘤共培养中，角质形成细胞中的桥粒基因敲低会显著增加邻近黑色素瘤细胞的增殖。在桥粒缺陷角质形成细胞预处理的培养基中观察到类似的黑色素瘤增殖增加。然后，相邻细胞中桥粒体突变的逐渐积累可能为黑色素瘤细胞的肿瘤转化做好准备。

据介绍，桥粒是跨膜蛋白复合物，在上皮和其他组织中促进细胞-细胞粘附。

附：英文原文

Title: Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation

Author: Baron, Maayan, Tagore, Mohita, Wall, Patrick, Zheng, Fan, Barkley, Dalia, Yanai, Itai, Yang, Jing, Kiuru, Maija, White, Richard M., Ideker, Trey

Issue&Volume: 2025-04-16

Abstract: Desmosomes are transmembrane protein complexes that contribute to cell–cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma, where desmosomes are mutated in more than 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes is associated with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these decreases in expression occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte and melanoma cocultures. Similar increases in melanoma proliferation are observed in media preconditioned with desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.

DOI: 10.1038/s41588-025-02163-9

Source: https://www.nature.com/articles/s41588-025-02163-9