An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth Journal Article


Authors: Atapattu, L.; Saha, N.; Chheang, C.; Eissman, M. F.; Xu, K.; Vail, M. E.; Hii, L.; Llerena, C.; Liu, Z.; Horvay, K.; Abud, H. E.; Kusebauch, U.; Moritz, R. L.; Ding, B. S.; Cao, Z.; Rafii, S.; Ernst, M.; Scott, A. M.; Nikolov, D. B.; Lackmann, M.; Janes, P. W.
Article Title: An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth
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. © 2016 Atapattu et al.
Journal Title: Journal of Experimental Medicine
Volume: 213
Issue: 9
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2016-08-22
Start Page: 1741
End Page: 1757
Language: English
DOI: 10.1084/jem.20151095
PROVIDER: scopus
PMCID: PMC4995075
PUBMED: 27503072
DOI/URL:
Notes: Article -- Export Date: 3 October 2016 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Dimitar B Nikolov
    87 Nikolov
  2. Kai Xu
    21 Xu
  3. Nayanendu Saha
    23 Saha