title: NAD⁺-Metabolizing Ectoenzymes in Remodeling Tumor-Host Interactions: The Human Myeloma Model.
abstract: Nicotinamide adenine dinucleotide (NAD⁺) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD⁺ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD⁺, belongs to the ectoenzymatic network generating intracellular Ca(2+)-active metabolites. Within this general framework, the extracellular conversion of NAD⁺ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo.
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. alberto.horenstein@unito.it.|CeRMS, University of Torino, Torino 10126, Italy. alberto.horenstein@unito.it.
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Horenstein
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. antonella.chillemi@unito.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Chillemi
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. valeria.quarona@unito.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Quarona
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. andrea.zito@unito.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zito
authors.affiliation: CeRMS, University of Torino, Torino 10126, Italy. roato78@libero.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Roato
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova 16148, Italy. fabiomorandi@ospedale-gaslini.ge.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Morandi
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova 16148, Italy. danilomarimpietri@ospedale-gaslini.ge.it.
authors.forename: Danilo
authors.initials: D
authors.lastname: Marimpietri
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. marina.bolzoni@unipr.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Bolzoni
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. denise.toscani@nemo.unipr.it.
authors.forename: Denise
authors.initials: D
authors.lastname: Toscani
authors.affiliation: Antibody & Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK. Robert.Oldham@soton.ac.uk.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Oldham
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy. massimiliano.cuccioloni@unicam.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.affiliation: Janssen Research & Development, LLC, Springhouse, PA 19477, USA. ksasser1@its.jnj.com.
authors.forename: A Kate
authors.initials: AK
authors.lastname: Sasser
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova 16148, Italy. vitopistoia@ospedale-gaslini.ge.it.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. nicola.giuliani@unipr.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. fabio.malavasi@unito.it.|CeRMS, University of Torino, Torino 10126, Italy. fabio.malavasi@unito.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
keywords: CD38; Daratumumab; NAD+; adenosine; ectoenzymes; multiple myeloma