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

Atapattu, L; Saha, N; Chheang, C; Eissmann, Moritz; Xu, K; Vail, Mary; Hii, L; Llerena, C; Liu, Z; Horvay, K; Abud, HE; Kusebauch, U; Moritz, RL; Ding, B-S; Cao, Z; Rafii, S; Ernst, Matthias; Scott, Andrew; Nikolov, DB; Lackmann, M; Janes, Peter

doi:10.26181/22424026.v1

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

journal contribution

posted on 2023-03-31, 03:20 authored by L Atapattu, N Saha, C Chheang, Moritz EissmannMoritz Eissmann, K Xu, Mary VailMary Vail, L Hii, C Llerena, Z Liu, K Horvay, HE Abud, U Kusebauch, RL Moritz, B-S Ding, Z Cao, S Rafii, Matthias ErnstMatthias Ernst, Andrew ScottAndrew Scott, DB Nikolov, M Lackmann, Peter JanesPeter Janes

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.

Funding

This work was supported by National Health and Medical Research Council (NHMRC), Australia (grants 384242, 1067609, and 1093304; fellowships to P.W. Janes [384285], M. Lackmann [1003908], M. Ernst [1079257], and A.M. Scott [1084178]; and scholarship to L. Atapattu [1017654]) and by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. Additional funding included an award to D.B. Nikolov from The Experimental Therapeutics Center of Memorial Sloan-Kettering, support from Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and National Institutes of Health grants R21CA185930 and R01 NS03848 (to D.B. Nikolov). x-ray diffraction experiments were conducted remotely at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines ID24, which are supported by a grant from the National Institute of General Medical Sciences (P41 GM103403) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under contract no. DE-AC02-06CH11357.

History

Publication Date

2016-08-08

Journal

Journal of Experimental Medicine

Volume

213

Issue

9

Pagination

17p. (p. 1741-1757)

Publisher

Rockefeller University Press

ISSN

1540-9538

Rights Statement

© 2016 Atapattu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).