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

Lakmali Atapattu, Nayanendu Saha, Chanly Chheang, Moritz F. Eissman, Kai Xu, Mary E. Vail, Linda Hii, Carmen Llerena, Zhanqi Liu, Katja Horvay, Helen E. Abud, Ulrike Kusebauch, Robert L. Moritz, Bi-Sen Ding, Zhongwei Cao, Shahin Rafii, Matthias Ernst, Andrew M. Scott, Dimitar B. Nikolov, Martin Lackmann & 1 others Peter W. Janes

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1741-1757
Number of pages17
JournalJournal of Experimental Medicine
Volume213
Issue number9
DOIs
Publication statusPublished - 8 Aug 2016

Keywords

  • solid tumors

Cite this

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. / An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 9. pp. 1741-1757.
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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.",
keywords = "solid tumors",
author = "Lakmali Atapattu and Nayanendu Saha and Chanly Chheang and Eissman, {Moritz F.} and Kai Xu and Vail, {Mary E.} and Linda Hii and Carmen Llerena and Zhanqi Liu and Katja Horvay and Abud, {Helen E.} and Ulrike Kusebauch and Moritz, {Robert L.} and Bi-Sen Ding and Zhongwei Cao and Shahin Rafii and Matthias Ernst and Scott, {Andrew M.} and Nikolov, {Dimitar B.} and Martin Lackmann and Janes, {Peter W.}",
year = "2016",
month = "8",
day = "8",
doi = "10.1084/jem.20151095",
language = "English",
volume = "213",
pages = "1741--1757",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
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}

Atapattu, L, Saha, N, Chheang, C, Eissman, MF, Xu, K, Vail, ME, Hii, L, Llerena, C, Liu, Z, Horvay, K, Abud, HE, Kusebauch, U, Moritz, RL, Ding, B-S, Cao, Z, Rafii, S, Ernst, M, Scott, AM, Nikolov, DB, Lackmann, M & Janes, PW 2016, 'An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth' Journal of Experimental Medicine, vol. 213, no. 9, pp. 1741-1757. https://doi.org/10.1084/jem.20151095

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

In: Journal of Experimental Medicine, Vol. 213, No. 9, 08.08.2016, p. 1741-1757.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

AU - Atapattu, Lakmali

AU - Saha, Nayanendu

AU - Chheang, Chanly

AU - Eissman, Moritz F.

AU - Xu, Kai

AU - Vail, Mary E.

AU - Hii, Linda

AU - Llerena, Carmen

AU - Liu, Zhanqi

AU - Horvay, Katja

AU - Abud, Helen E.

AU - Kusebauch, Ulrike

AU - Moritz, Robert L.

AU - Ding, Bi-Sen

AU - Cao, Zhongwei

AU - Rafii, Shahin

AU - Ernst, Matthias

AU - Scott, Andrew M.

AU - Nikolov, Dimitar B.

AU - Lackmann, Martin

AU - Janes, Peter W.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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.

AB - 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.

KW - solid tumors

U2 - 10.1084/jem.20151095

DO - 10.1084/jem.20151095

M3 - Article

VL - 213

SP - 1741

EP - 1757

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 9

ER -