Baron Maayan, Tagore Mohita, Wall Patrick, Zheng Fan, Barkley Dalia, Yanai Itai, Yang Jing, Kiuru Maija, White Richard M, Ideker Trey
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Genet. 2025 May;57(5):1179-1188. doi: 10.1038/s41588-025-02163-9. Epub 2025 Apr 16.
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.
桥粒是跨膜蛋白复合物，有助于上皮组织和其他组织中的细胞间黏附。在此，我们报告了人类癌症中桥粒频繁发生基因改变的发现，其中最强的信号出现在皮肤黑色素瘤中，超过70%的病例中桥粒发生了突变。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显著降低有关。空间转录组学和蛋白质免疫荧光分析表明，这些表达的降低发生在微环境中的角质形成细胞而非原发性黑色素瘤细胞中。为进一步支持微环境起源，我们发现在角质形成细胞和黑色素瘤共培养中，角质形成细胞中桥粒基因敲低会导致相邻黑色素瘤细胞的增殖显著增加。在用缺乏桥粒的角质形成细胞预处理的培养基中也观察到黑色素瘤增殖的类似增加。因此，相邻细胞中桥粒突变的逐渐积累可能使黑色素瘤细胞易于发生肿瘤转化。
