Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/16704
Title: An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth
Authors: Atapattu, Lakmali;Saha, Nayanendu;Chheang, Chanly;Eissman, Moritz F;Xu, Kai;Vail, Mary E;Hii, Linda;Llerena, Carmen;Liu, Zhanqi;Horvay, Katja;Abud, Helen E;Kusebauch, Ulrike;Moritz, Robert L;Ding, Bi-Sen;Cao, Zhongwei;Rafii, Shahin;Ernst, Matthias;Scott, Andrew M;Nikolov, Dimitar B;Lackmann, Martin;Janes, Peter W
Issue Date: 22-Aug-2016
EDate: 2016-08-08
Citation: Journal of Experimental Medicine 2016; 213(9): 1741-1757
Abstract: The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16704
DOI: 10.1084/jem.20151095
ORCID: 0000-0003-4312-1358
0000-0001-7653-8905
0000-0002-0851-0115
0000-0002-5551-061X
0000-0001-6829-4840
0000-0002-4420-5150
0000-0003-3792-4023
0000-0002-3216-9447
0000-0002-9039-1097
PubMed URL: https://www.ncbi.nlm.nih.gov/pubmed/27503072
Type: Journal Article
Subjects: ADAM10 Protein
Neoplasms, Experimental
Neoplastic Stem Cells
Appears in Collections:Journal articles

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