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.
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Lakmali
authors: 0000-0001-7653-8905
authors: L
authors: Atapattu
authors: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors: Nayanendu
authors: N
authors: Saha
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Chanly
authors: 0000-0002-0851-0115
authors: C
authors: Chheang
authors: Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors: Moritz F
authors: MF
authors: Eissman
authors: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors: Kai
authors: K
authors: Xu
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Mary E
authors: 0000-0002-5551-061X
authors: ME
authors: Vail
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Linda
authors: 0000-0001-6829-4840
authors: L
authors: Hii
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Carmen
authors: C
authors: Llerena
authors: Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors: Zhanqi
authors: 0000-0003-4312-1358
authors: Z
authors: Liu
authors: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Katja
authors: 0000-0002-4420-5150
authors: K
authors: Horvay
authors: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Helen E
authors: 0000-0003-3792-4023
authors: HE
authors: Abud
authors: Institute for Systems Biology, Seattle, WA 98109.
authors: Ulrike
authors: U
authors: Kusebauch
authors: Institute for Systems Biology, Seattle, WA 98109.
authors: Robert L
authors: 0000-0002-3216-9447
authors: RL
authors: Moritz
authors: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors: Bi-Sen
authors: BS
authors: Ding
authors: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors: Zhongwei
authors: Z
authors: Cao
authors: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors: Shahin
authors: S
authors: Rafii
authors: Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors: Matthias
authors: M
authors: Ernst
authors: Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors: Andrew M
authors: AM
authors: Scott
authors: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors: Dimitar B
authors: DB
authors: Nikolov
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Martin
authors: M
authors: Lackmann
authors: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia peter.janes@monash.edu.
authors: Peter W
authors: 0000-0002-9039-1097
authors: PW
authors: Janes
mesh_terms: D000072197:ADAM10 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D000072198:ADAM17 Protein / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051880:Receptors, Notch / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D051880:Receptors, Notch; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein