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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 o...

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Detalles Bibliográficos
Autores principales: Baron, Maayan, Tagore, Mohita, Wall, Patrick, Zheng, Fan, Barkley, Dalia, Yanai, Itai, Yang, Jing, Kiuru, Maija, White, Richard M., Ideker, Trey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541613/
https://www.ncbi.nlm.nih.gov/pubmed/37786690
http://dx.doi.org/10.1101/2023.09.19.558457
Descripción
Sumario: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 over 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations on desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma tumor cells. In further support of a microenvironmental origin, we find that loss-of-function knockdowns of the desmosome in keratinocytes yield markedly increased proliferation of adjacent melanocytes in keratinocyte/melanocyte co-cultures. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanocytes for neoplastic transformation.