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

9 Citations (Scopus)

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 1 2017

Fingerprint

Desmoglein 2
Keratinocytes
Squamous Cell Carcinoma
Tumors
Neoplasms
Tumor Microenvironment
Fluorescence
Cells
Fibroblasts
Epidermal Growth Factor Receptor
Desmosomal Cadherins
Extracellular Vesicles
Epithelial Cells
Matrix Metalloproteinase Inhibitors
Cell proliferation
Sorting
Blood Cells
Flow Cytometry
Proteins
Blood

Keywords

  • EGFR
  • Exosome
  • Fibroblast
  • HNSCC

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., ... 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

Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes. / Overmiller, Andrew M.; Pierluissi, Jennifer A.; Wermuth, Peter J.; Sauma, Sami; Martinez-Outschoorn, Ubaldo; Tuluc, Madalina; Luginbuhl, Adam; Curry, Joseph; Harshyne, Larry A.; Wahl, James K; South, Andrew P.; Mahoney, M. G.

In: FASEB Journal, Vol. 31, No. 8, 01.08.2017, p. 3412-3424.

Research output: Contribution to journalArticle

Overmiller, AM, Pierluissi, JA, Wermuth, PJ, Sauma, S, Martinez-Outschoorn, U, Tuluc, M, Luginbuhl, A, Curry, J, Harshyne, LA, Wahl, JK, South, AP & Mahoney, MG 2017, 'Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes', FASEB Journal, vol. 31, no. 8, pp. 3412-3424. https://doi.org/10.1096/fj.201601138RR
Overmiller AM, Pierluissi JA, Wermuth PJ, Sauma S, Martinez-Outschoorn U, Tuluc M et al. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes. FASEB Journal. 2017 Aug 1;31(8):3412-3424. https://doi.org/10.1096/fj.201601138RR
Overmiller, Andrew M. ; Pierluissi, Jennifer A. ; Wermuth, Peter J. ; Sauma, Sami ; Martinez-Outschoorn, Ubaldo ; Tuluc, Madalina ; Luginbuhl, Adam ; Curry, Joseph ; Harshyne, Larry A. ; Wahl, James K ; South, Andrew P. ; Mahoney, M. G. / Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes. In: FASEB Journal. 2017 ; Vol. 31, No. 8. pp. 3412-3424.
@article{ad12e990312547708b62b691466a5d93,
title = "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. 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",
keywords = "EGFR, Exosome, Fibroblast, HNSCC",
author = "Overmiller, {Andrew M.} and Pierluissi, {Jennifer A.} and Wermuth, {Peter J.} and Sami Sauma and Ubaldo Martinez-Outschoorn and Madalina Tuluc and Adam Luginbuhl and Joseph Curry and Harshyne, {Larry A.} and Wahl, {James K} and South, {Andrew P.} and Mahoney, {M. G.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1096/fj.201601138RR",
language = "English (US)",
volume = "31",
pages = "3412--3424",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "8",

}

TY - JOUR

T1 - Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

AU - Overmiller, Andrew M.

AU - Pierluissi, Jennifer A.

AU - Wermuth, Peter J.

AU - Sauma, Sami

AU - Martinez-Outschoorn, Ubaldo

AU - Tuluc, Madalina

AU - Luginbuhl, Adam

AU - Curry, Joseph

AU - Harshyne, Larry A.

AU - Wahl, James K

AU - South, Andrew P.

AU - Mahoney, M. G.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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

AB - 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

KW - EGFR

KW - Exosome

KW - Fibroblast

KW - HNSCC

UR - http://www.scopus.com/inward/record.url?scp=85026803697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026803697&partnerID=8YFLogxK

U2 - 10.1096/fj.201601138RR

DO - 10.1096/fj.201601138RR

M3 - Article

VL - 31

SP - 3412

EP - 3424

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 8

ER -