Desmosomes in Human Disease

Najor, Nicole A.

doi:10.1146/annurev-pathol-020117-044030

Cited by 55 publications

(60 citation statements)

References 154 publications

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“…Such CTC clusters displayed an increase in the junctional cytoplasmic plaque protein plakoglobin (γ-catenin) 31 . Plakoglobin is a paralogue of β-catenin that, in addition to its interaction with adherens junctions, is a key component of desmosomes, a specialized epithelial cell–cell adhesion structure 32 . When compared with β-catenin (whose overexpression enhances tumorigenesis), plakoglobin is associated mostly with tumor suppression 33 .…”

Section: Intermediate Epithelial-to-mesenchymal Transition States CImentioning

confidence: 99%

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

2018

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Changes in cell adhesion and motility are considered key elements in determining the development of invasive and metastatic tumors. Co-opting the epithelial-to-mesenchymal transition (EMT) process, which is known to occur during embryonic development, and the associated changes in cell adhesion properties in cancer cells are considered major routes for tumor progression. More recent in vivo studies in tumor tissues and circulating tumor cell clusters suggest a stepwise EMT process rather than an “all-or-none” transition during tumor progression. In this commentary, we addressed the molecular mechanisms underlying the changes in cell adhesion and motility and adhesion-mediated signaling and their relationships to the partial EMT states and the acquisition of stemness traits by cancer cells.

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Section: Intermediate Epithelial-to-mesenchymal Transition States CImentioning

confidence: 99%

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

2018

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“…Ref. 23 ). Therefore, we aimed to determine the role of desmosomes in the different "compactness" of the HaCaT and HaSKpwC7 cells.…”

Section: Haskpwc7 and Hacat Have Comparable Plating Efficiency But DImentioning

confidence: 99%

Characterisation of the novel spontaneously immortalized and invasively growing human skin keratinocyte line HaSKpw

Loriè

Stricker

Plitta-Michalak

et al. 2020

Sci Rep

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We here present the spontaneously immortalised cell line, HaSKpw, as a novel model for the multistep process of skin carcinogenesis. HaSKpw cells were established from the epidermis of normal human adult skin that, without crisis, are now growing unrestricted and feeder-independent. At passage 22, clonal populations were established and clone7 (HaSKpwC7) was further compared to the also spontaneously immortalized HaCaT cells. As important differences, the HaSKpw cells express wild-type p53, remain pseudodiploid, and show a unique chromosomal profile with numerous complex aberrations involving chromosome 20. In addition, HaSKpw cells overexpress a pattern of genes and miRNAs such as KRT34, LOX, S100A9, miR21, and miR155; all pointing to a tumorigenic status. In concordance, HaSKpw cells exhibit reduced desmosomal contacts that provide them with increased motility and a highly migratory/invasive phenotype as demonstrated in scratch- and Boyden chamber assays. In 3D organotypic cultures, both HaCaT and HaSKpw cells form disorganized epithelia but only the HaSKpw cells show tumorcell-like invasive growth. Together, HaSKpwC7 and HaCaT cells represent two spontaneous (non-genetically engineered) “premalignant” keratinocyte lines from adult human skin that display different stages of the multistep process of skin carcinogenesis and thus represent unique models for analysing skin cancer development and progression.

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“…N = 8, 13, 16, respectively. Tumour volume in mm3 : Day 7 (GFP, 2.0 ± 1.4; Dsg2/GFP, 14.5 ± 4.8; Dsg2cacs/GFP, 2.2 ± 1.3); Day 9 (GFP, 7.5 ± 3.7; Dsg2/GFP, 96.3 ± 31.3; Dsg2cacs/GFP, 29.1 ± 9.4); Day 14 (GFP, 57.9 ± 19.0; Dsg2/GFP, 323.3 ± 45.3; Dsg2cacs/GFP, 104.4 ± 17.2); Day 17 (GFP, 81.3 ± 22.4; Dsg2/GFP, 596.2 ± 133.7; Dsg2cacs/GFP, 146.4 ± 25.8); Day 21 (GFP, 157.1 ± 39.8 Dsg2/GFP, 768.0 ± 162.5; Dsg2cacs/GFP, 279.5 ± 42.9). *, A431-Dsg2/GFP vs A431-GFP; Δ, A431-Dsg2/GFP vs A431-Dsg2cacs/GFP.…”

mentioning

confidence: 99%

miRNA‐ and cytokine‐associated extracellular vesicles mediate squamous cell carcinomas

Flemming

Hill

Haque

et al. 2020

J of Extracellular Vesicle

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Exosomes, or small extracellular vesicles (sEVs), serve as intercellular messengers with key roles in normal and pathological processes. Our previous work had demonstrated that Dsg2 expression in squamous cell carcinoma (SCC) cells enhanced both sEV secretion and loading of pro-mitogenic cargo. In this study, using wild-type Dsg2 and a mutant form that is unable to be palmitoylated (Dsg2cacs), we investigated the mechanism by which Dsg2 modulates SCC tumour development and progression through sEVs. We demonstrate that palmitoylation was required for Dsg2 to regulate sub-cellular localisation of lipid raft and endosomal proteins necessary for sEV biogenesis. Pharmacological inhibition of the endosomal pathway abrogated Dsg2-mediated sEV release. In murine xenograft models, Dsg2-expressing cells generated larger xenograft tumours as compared to cells expressing GFP or Dsg2cacs. Co-treatment with sEVs derived from Dsg2over-expressing cells increased xenograft size. Cytokine profiling revealed, Dsg2 enhanced both soluble and sEV-associated IL-8 and miRNA profiling revealed, Dsg2 down-regulated both cellular and sEV-loaded miR-146a. miR-146a targets IRAK1, a serine-threonine kinase involved in IL-8 signalling. Treatment with a miR-146a inhibitor up-regulated both IRAK1 and IL-8 expression. RNAseq analysis of HNSCC tumours revealed a correlation between Dsg2 and IL-8. Finally, elevated IL-8 plasma levels were detected in a subset of HNSCC patients who did not respond to immune checkpoint therapy, suggesting that these patients may benefit from prior anti-IL-8 treatment. In summary, these results suggest that intercellular communication through cell-cell adhesion, cytokine release and secretion of EVs are coordinated, and critical for tumour growth and development, and may serve as potential prognostic markers to inform treatment options.

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Desmosomes in Human Disease

Cited by 55 publications

References 154 publications

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

Characterisation of the novel spontaneously immortalized and invasively growing human skin keratinocyte line HaSKpw

miRNA‐ and cytokine‐associated extracellular vesicles mediate squamous cell carcinomas

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