Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation Journal Article
| Authors: | Baron, M.; Tagore, M.; Wall, P.; Zheng, F.; Barkley, D.; Yanai, I.; Yang, J.; Kiuru, M.; White, R. M.; Ideker, T. |
| Article Title: | Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation |
| 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; mutation; nonhuman; cell proliferation; biological marker; mouse; metabolism; gene; melanoma; gene expression; skin neoplasms; melanocyte; immunofluorescence; pathology; cell line, tumor; transcriptomics; keratinocyte; gene expression regulation; gene expression regulation, neoplastic; skin tumor; membrane protein; tumor cell line; mutation rate; cytokeratin 14; cadherin; keratinocytes; short hairpin rna; tumor microenvironment; desmosome; transcription factor sox10; desmoplakin; desmosomes; gene knockdown; humans; human; article; mutational load; single cell rna seq; multiomics; desmoglein 2; jup protein; dsp gene; perp gene |
| Journal Title: | Nature Genetics |
| Volume: | 57 |
| Issue: | 5 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-05-01 |
| Start Page: | 1179 |
| End Page: | 1188 |
| Language: | English |
| DOI: | 10.1038/s41588-025-02163-9 |
| PUBMED: | 40240879 |
| PROVIDER: | scopus |
| PMCID: | PMC12204749 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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