Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

Abstract

Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90 + fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.-Overmiller, A.

HSP‐enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells

“…We showed highly surviving cancer stem‐like cells to robustly secrete EpCAM‐contained EVs . It was also shown that levels of epidermal growth factor (EGFR) were elevated in serum EVs as well as primary tumors in patients suffering from head and neck squamous cell carcinoma . Notably, HSP90 was also found in EVs secreted by cancer cells …”

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

“…The stop codon of the human Dsg2 cDNA was removed and sub-cloned into vector pEGFP-N1 (Clontech, Mountain View, CA) upstream of the GFP as previously described in detail [13,20,21]. For Dsg2cacs cDNA, two cysteine point mutations were generated using the QuikChange site directed mutagenesis kit (Stratagene, San Diego, CA) [20].…”

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression

“…The non-cell autonomous effect of Dsg2 could be explained by increased urokinase-type plasminogen activator and/or IL-6 production or by transfer of the upregulated receptors by extracellular vesicles or exosomes by Dsg2-expressing cells (Figure 4). In this regard, we have previously described that Dsg2 can alter the number and protein content of extracellular vesicles released by keratinocytes (Overmiller et al, 2017).…”