Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

Andrew M. Overmiller, Jennifer A. Pierluissi, Peter J. Wermuth, Sami Sauma, Ubaldo Martinez-Outschoorn, Madalina Tuluc, Adam Luginbuhl, Joseph Curry, Larry A. Harshyne, James K. Wahl, Andrew P. South, M. G. Mahoney

Research output: Contribution to journalArticle

18 Scopus citations

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. 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. FASEB J. 31, 3412–3424 (2017). www.fasebj.org

Original languageEnglish (US)
Pages (from-to)3412-3424
Number of pages13
JournalFASEB Journal
Volume31
Issue number8
DOIs
StatePublished - Aug 2017

Keywords

  • EGFR
  • Exosome
  • Fibroblast
  • HNSCC

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    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., South, A. P., & Mahoney, M. G. (2017). Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes. FASEB Journal, 31(8), 3412-3424. https://doi.org/10.1096/fj.201601138RR