Desmosome突变影响肿瘤微环境以促进黑色素瘤增殖。

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

Desmosome是一种跨膜蛋白复合物,有助于上皮和其他组织中的细胞-细胞粘附。在这里,我们报道了在人类癌症中桥粒频繁发生基因改变的发现,其中在皮肤黑色素瘤中发现的信号最强,超过70%的病例中桥粒发生突变。在原发性但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。空间转录组学分析表明,这些表达减少发生在微环境中的角质形成细胞中,而不是原发性黑色素瘤肿瘤细胞中。为了进一步支持微环境起源,我们发现角质形成细胞中桥粒的功能缺失敲除导致角质形成细胞/黑素细胞共培养物中相邻黑素细胞的增殖显著增加。因此,桥粒突变在邻近细胞中的逐渐积累可能为黑色素细胞的肿瘤转化提供条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.

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 >70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these expression decreases 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/melanoma co-cultures. Similar increases in melanoma proliferation are observed in media preconditioned by desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.

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