Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

• Published in: The FASEB journal Vol. 31; no. 8; p. 3412
• Main Authors: Overmiller, Andrew M, Pierluissi, Jennifer A, Wermuth, Peter J, Sauma, Sami, Martinez-Outschoorn, Ubaldo, Tuluc, Madalina, Luginbuhl, Adam, Curry, Joseph, Harshyne, Larry A, Wahl, 3rd, James K, South, Andrew P, Mahoney, Mỹ G
• Format: Journal Article
• Language: English
• Published: United States 01.08.2017
• Subjects: Carcinoma, Squamous Cell - metabolism; Cells, Cultured; Desmoglein 2 - genetics; Desmoglein 2 - metabolism; Extracellular Vesicles - metabolism; Gene Expression Regulation, Neoplastic - physiology; Humans; Keratinocytes - metabolism; Keratinocytes - pathology; fibroblast; exosome; HNSCC; EGFR
• ISSN: 1530-6860
• DOI: 10.1096/fj.201601138RR

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. 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. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K. III, South, A. P., Mahoney, M. G. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.