Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.

Autor:	Baron M; Department of Medicine, University of California San Diego, La Jolla, CA USA.; co-authors., Tagore M; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY USA.; co-authors., Wall P; Department of Medicine, University of California San Diego, La Jolla, CA USA., Zheng F; Department of Medicine, University of California San Diego, La Jolla, CA USA., Barkley D; Institute for Computational Medicine, NYU School of Medicine, New York, NY USA., Yanai I; Institute for Computational Medicine, NYU School of Medicine, New York, NY USA., Yang J; Department of Pharmacology, University of California San Diego, La Jolla, CA USA., Kiuru M; Depts. of Dermatology and Pathology, University of California Davis, Sacramento, CA USA., White RM; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY USA.; Ludwig Cancer Research, University of Oxford, Oxford, UK., Ideker T; Department of Medicine, University of California San Diego, La Jolla, CA USA.; Department of Bioengineering, University of California San Diego, La Jolla, CA USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 17. Date of Electronic Publication: 2024 Oct 17.
DOI:	10.1101/2023.09.19.558457
Abstrakt:	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. Competing Interests: Declaration of Interests: T.I. is a co-founder, member of the advisory board, and has an equity interest in Data4Cure and Serinus Biosciences. T.I. is a consultant for and has an equity interest in Ideaya BioSciences. The terms of these arrangements have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies. R.M.W. is a paid consultant to N-of-One, a subsidiary of Qiagen.
Databáze:	MEDLINE
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