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Title: An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth
Austin 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 
Affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer, New York, NY, USA
Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
Institute for Systems Biology, Seattle, WA, USA
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Issue Date: 22-Aug-2016 2016-08-08
Publication information: 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.
DOI: 10.1084/jem.20151095
ORCID: 0000-0003-4312-1358
PubMed URL:
Type: Journal Article
Subjects: ADAM10 Protein
Neoplasms, Experimental
Neoplastic Stem Cells
Appears in Collections:Journal articles

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