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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291159 | GEO | 2025/03/05

REPOSITORIES: GEO

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

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.

2025-03-08 | GSE291160 | GEO

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 [Spatial transcriptomics]

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

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Disruption of tuftelin 1, a desmosome associated protein,causesskin fragility, woolly hair and palmoplantar keratoderma

Project description:Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair and mild palmoplantar keratoderma, but without a cardiac phenotype, we identified a homozygous splice site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of tuftelin 1 protein. Patients’ skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients’ phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma.

2023-10-30 | GSE237986 | GEO

Proximity mapping of desmosomes reveals a striking maturation-dependent shift in their molecular neighbourhood

Project description:Desmosomes are multiprotein adhesion complexes that link intermediate filaments to the plasma membrane, ensuring the mechanical integrity of cells across tissues, but how they participate in the wider signalling network to exert their full function is unclear. To investigate this we performed multiplexed proximity biotinylation (BioID). The combined interactomes of the essential desmosomal proteins desmocollin 2a, plakoglobin and plakophilin 2a (Pkp2a) in Madin-Darby canine kidney epithelial cells were mapped and their differences and commonalities characterised as desmosome matured from Ca2+-dependence to the mature, Ca2+-independent, hyper-adhesive state, which predominates in tissues. Results suggest distinct roles of individual desmosomal proteins in linking to cellular signalling pathways that alter substantially when cells change their adhesion state. Moreover, we find support for our dualistic concept of desmosomes in which the properties of Pkp2a differ from those of the other, more stable proteins. The data provide a requisite resource to unravel the nature of desmosomes.

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The effects of TGM1 Mutations in HEK293T and HaCaT cells

Project description:Autosomal recessive congenital ichthyosis (ARCI) is a group of rare inherited skin disorders characterized by remarkable hyperkeratosis. Transglutaminase 1 (TGM1) mutations have been reported to be involved in four different phenotypes of ARCI, including lamellar ichthyosis (LI), non-bullous congenital ichthyosiform erythroderma (NBCIE), bathing suit ichthyosis (BSI), and self-improving collodion ichthyosis (SICI) according to the clinical presentation and histopathology. TGM1 has been found as a defective gene in a large amount of patients with LI and some patients with NBCIE, BSI and SICI. To further understand the effect of TGM1 mutations in epidermal cells development, we performed the transcriptome analysis of HEK293T and HaCaT cells transfected with TGM1 shRNA, TGM1 wild-type and mutant clones. The transcriptomic analysis revealed the effects of TGM1 on cell-cell interaction by suppressing genes involved in the gap junctions, tight junctions and desmosomes. These findings suggested that the TGM1 deficiency disturbed the balance of keratinocytes proliferation and differentiation processes and impaired the epithelial barrier function. The results provided the basis for further understanding on the etiology of ARCI. To explore the functional impacts on some of the TGM1mutations identified, we cloned and transfected the TGM1 wild type and mutant clones into HEK293T and HaCaT cells. R142C and R348X sequence mutations observed in ARCI (Autosomal recessive congenital ichthyosis) patients were generated. The shRNA targeting TGM1 and a scrambled negative control were obtained from Invitrogen (Carlsbad, CA). The293T and HaCaT cells were transfected with over-expression clones carry either wild-type or mutated TGM1sequence. Cells were harvested 48 hours post-transfection.

2015-12-31 | E-GEOD-70859 | biostudies-arrayexpress

Plakophilin 1 enhances MYC expression to promote squamous cell lung cancer

Project description:Plakophilin 1 (PKP1) is a component of desmosomes. Although desmosome function loss has been associated with increased cell migration and pro-oncogenic activity, we previously observed PKP1 overexpression in squamous cell lung cancer (SqCLC). We developed in vitro and in vivo functional models of PKP1 gain/loss in SqCLC to explore this paradox. Greater cell dissemination but reduced cell proliferation was observed in CRISPR-Cas9 PKP1-knockout clones. PKP1 expression promoted cell proliferation, cell survival, and in vivo xenograft engraftment, and these pro-oncogenic activities were mediated by the functional relationship of PKP1 with MYC. PKP1 bound to the 5’UTR of MYC mRNA, enhancing MYC translation, and MYC bound directly to the PKP1 promoter, enhancing PKP1 transcription. We propose PKP1 as a novel oncogene in SqCLC and a post-transcriptional regulator of MYC. PKP1 may be a valuable diagnostic biomarker and potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may indirectly target MYC, a primary anti-cancer target.

2020-05-10 | GSE106770 | GEO

The effects of TGM1 Mutations in HEK293T and HaCaT cells

2015-12-31 | GSE70859 | GEO

TNYA0042: TN-401 dose-dependent efficacy study at about 10 weeks in Pkp2-cKO ARVC mouse model

Project description:Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

2024-02-23 | GSE253224 | GEO

TNYA0016: Time-dependent transcriptional effects of PKP2 mRNA knockdown in wild-type human iPSC-CMs

2024-02-23 | GSE253223 | GEO