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Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation [Spatial transcriptomics]

ABSTRACT: Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation [Spatial transcriptomics]

PROVIDER: PRJNA1232113 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32576400_1.fastq.gz	Fastqsanger.gz
	SRR32576400_2.fastq.gz	Fastqsanger.gz
	SRR32576500_1.fastq.gz	Fastqsanger.gz
	SRR32576500_2.fastq.gz	Fastqsanger.gz
	SRR32576401_1.fastq.gz	Fastqsanger.gz

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Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation [Spatial transcriptomics]

Project 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 >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.

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Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation [scRNA-seq]

Project description:Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation [scRNA-seq]

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Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.

Project 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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