title: Identification of thyroid tumor cell vulnerabilities through a siRNA-based functional screening.
abstract: The incidence of thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of thyroid tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3-1). We identified a panel of hit genes whose silencing interferes with the growth of tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for thyroid tumor cells, as their inhibition reduced the viability of several thyroid tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of thyroid tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies.
authors.affiliation: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anania
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparri
authors.affiliation: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cetti
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Fraietta
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: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.affiliation: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Mazzoni
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Re
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ukmar
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Camisasca
authors.affiliation: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pagliardini
authors.affiliation: Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pierotti
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
mesh_terms: D015153:Blotting, Western; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D020756:Coatomer Protein / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling / Q000379:methods; D019940:Genes, bcl-1 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering; D017423:Sequence Analysis, RNA / Q000379:methods; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D014162:Transfection
chemical_list: D020756:Coatomer Protein; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases
keywords: COPZ1; Cyclin D1; MASTL; non-oncogene addiction; thyroid cancer