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.
N1 - Funding Information:
This work was supported, in part, by the U.S. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant AR056067 to M.G.M.), and the Thomas Jefferson University Dean’s Transformational Science Award (to M.G.M.). Confocal microscopy was performed in the Bioimaging Core (SKCC; NCI 5 P30 CA-56036). Special thanks to M. Y. Covarrubias (Bioimaging Shared Resource of the Sidney Kimmel Cancer Center, Thomas Jefferson University) for technical assistance and advice. The authors declare no conflicts of interest
Publisher Copyright:
© FASEB
PY - 2017/8
Y1 - 2017/8
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
C2 - 28438789
AN - SCOPUS:85026803697
SN - 0892-6638
VL - 31
SP - 3412
EP - 3424
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -