title: Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers.
abstract: Netrin-1 has been shown to be up-regulated in a fraction of human cancers as a mechanism to allow these tumors to escape the pro-apoptotic activity of some of its main dependence receptors, the UNC5 homologs (UNC5H). Here we identify the V-2 domain of netrin-1 to be important for its interaction with the Ig1/Ig2 domains of UNC5H2. We generate a humanized anti-netrin-1 antibody that disrupts the interaction between netrin-1 and UNC5H2 and triggers death of netrin-1-expressing tumor cells in vitro. We also present evidence that combining the anti-netrin-1 antibody with epidrugs such as decitabine could be effective in treating tumors showing no or modest netrin-1 expression. These results support that this antibody is a promising drug candidate.
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors: Mélodie
authors: M
authors: Grandin
authors: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
authors: Markus
authors: M
authors: Meier
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors: Jean Guy
authors: JG
authors: Delcros
authors: Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany; Centre for Ecology, Evolution and Environmental Changes, Faculdade de Ciências, Universidade de Lisboa, Lisbon 1749-016, Portugal.
authors: Denise
authors: D
authors: Nikodemus
authors: Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany.
authors: Raphael
authors: R
authors: Reuten
authors: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada; Department of Microbiology, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
authors: Trushar R
authors: TR
authors: Patel
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: David
authors: D
authors: Goldschneider
authors: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
authors: George
authors: G
authors: Orriss
authors: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
authors: Natalie
authors: N
authors: Krahn
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors: Amina
authors: A
authors: Boussouar
authors: Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: Riad
authors: R
authors: Abes
authors: Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: Yann
authors: Y
authors: Dean
authors: Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: David
authors: D
authors: Neves
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: Agnes
authors: A
authors: Bernet
authors: Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
authors: Stephane
authors: S
authors: Depil
authors: Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany.
authors: Fiona
authors: F
authors: Schneiders
authors: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straβe 10, Berlin 13092, Germany.
authors: Kate
authors: K
authors: Poole
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors: Robert
authors: R
authors: Dante
authors: Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany; Centre for Ecology, Evolution and Environmental Changes, Faculdade de Ciências, Universidade de Lisboa, Lisbon 1749-016, Portugal.
authors: Manuel
authors: M
authors: Koch
authors: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France. Electronic address: patrick.mehlen@lyon.unicancer.fr.
authors: Patrick
authors: P
authors: Mehlen
authors: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada. Electronic address: jorg.stetefeld@ad.manitoba.ca.
authors: Jörg
authors: J
authors: Stetefeld
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C115727:UNC5C protein, human; D000075388:Netrin-1