Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
Menée à l'aide de cocultures de kératinocytes et de mélanomes ainsi qu'à partir de l'analyse transcriptomique spatiale et de l'immunomarquage d'échantillons tumoraux, cette étude met en évidence un mécanisme par lequel des mutations au niveau des gènes codant pour des protéines impliquées dans la formation des desmosomes (zones de jonction intercellulaire) favorisent la prolifération des cellules cancéreuses en modifiant le microenvironnement tumoral
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.
Nature Genetics , résumé 2025