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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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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
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author Baron, Maayan
Tagore, Mohita
Wall, Patrick
Zheng, Fan
Barkley, Dalia
Yanai, Itai
Yang, Jing
Kiuru, Maija
White, Richard M.
Ideker, Trey
author_facet Baron, Maayan
Tagore, Mohita
Wall, Patrick
Zheng, Fan
Barkley, Dalia
Yanai, Itai
Yang, Jing
Kiuru, Maija
White, Richard M.
Ideker, Trey
author_sort Baron, Maayan
collection PubMed
description 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.
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spelling pubmed-105416132023-10-02 Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation Baron, Maayan Tagore, Mohita Wall, Patrick Zheng, Fan Barkley, Dalia Yanai, Itai Yang, Jing Kiuru, Maija White, Richard M. Ideker, Trey bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-09-22 /pmc/articles/PMC10541613/ /pubmed/37786690 http://dx.doi.org/10.1101/2023.09.19.558457 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Baron, Maayan
Tagore, Mohita
Wall, Patrick
Zheng, Fan
Barkley, Dalia
Yanai, Itai
Yang, Jing
Kiuru, Maija
White, Richard M.
Ideker, Trey
Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title_full Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title_fullStr Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title_full_unstemmed Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title_short Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
title_sort desmosome mutations impact the tumor microenvironment to promote melanoma proliferation
topic Article
url 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
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