title: Notch signaling drives multiple myeloma induced osteoclastogenesis.
abstract: Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Thümmler
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mirandola
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Garavelli
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Apicella
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lazzari
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Marialuigia
authors.initials: M
authors.lastname: Lancellotti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Platonova
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Moeed
authors.initials: M
authors.lastname: Akbar
authors.affiliation: Division of Hematology and Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, TX, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiriva-Internati
authors.affiliation: Beatson West of Scotland Cancer Centre, Haemato-oncology Service, Gartnavel Hospital, Glasgow, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Soutar
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano; Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Goodyear
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Chiaramonte
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D053245:RANK Ligand; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins