Please use this identifier to cite or link to this item:
https://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 | 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 | Date: | 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. | URI: | https://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 |
Journal: | Journal of Experimental Medicine | PubMed URL: | https://pubmed.ncbi.nlm.nih.gov/27503072 | Type: | Journal Article | Subjects: | ADAM10 Protein Neoplasms, Experimental Neoplastic Stem Cells |
Appears in Collections: | Journal articles |
Show full item record
Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.