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

Overview

MeSH Major

  • ADAM10 Protein
  • Neoplasms, Experimental
  • Neoplastic Stem Cells

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.

publication date

  • January 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4995075

Digital Object Identifier (DOI)

  • 10.1084/jem.20151095

PubMed ID

  • 27503072

Additional Document Info

start page

  • 1741

end page

  • 57

volume

  • 213

number

  • 9