126 results on '"Sette, Giovanni"'
Search Results
2. L1077P CFTR pathogenic variant function rescue by Elexacaftor–Tezacaftor–Ivacaftor in cystic fibrosis patient-derived air–liquid interface (ALI) cultures and organoids: in vitro guided personalized therapy of non-F508del patients
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Lo Cicero, Stefania, Castelli, Germana, Blaconà, Giovanna, Bruno, Sabina Maria, Sette, Giovanni, Pigliucci, Riccardo, Villella, Valeria Rachela, Esposito, Speranza, Zollo, Immacolata, Spadaro, Francesca, Maria, Ruggero De, Biffoni, Mauro, Cimino, Giuseppe, Amato, Felice, Lucarelli, Marco, and Eramo, Adriana
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- 2023
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3. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells
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Orienti, Isabella, Salvati, Valentina, Sette, Giovanni, Zucchetti, Massimo, Bongiorno-Borbone, Lucilla, Peschiaroli, Angelo, Zolla, Lello, Francescangeli, Federica, Ferrari, Mariella, Matteo, Cristina, Bello, Ezia, Di Virgilio, Antonio, Falchi, Mario, De Angelis, Maria Laura, Baiocchi, Marta, Melino, Gerry, De Maria, Ruggero, Zeuner, Ann, and Eramo, Adriana
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- 2019
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4. A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors
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Orienti, Isabella, Francescangeli, Federica, De Angelis, Maria Laura, Fecchi, Katia, Bongiorno-Borbone, Lucilla, Signore, Michele, Peschiaroli, Angelo, Boe, Alessandra, Bruselles, Alessandro, Costantino, Angelita, Eramo, Adriana, Salvati, Valentina, Sette, Giovanni, Contavalli, Paola, Zolla, Lello, Oki, Toshihiko, Kitamura, Toshio, Spada, Massimo, Giuliani, Alessandro, Baiocchi, Marta, La Torre, Filippo, Melino, Gerry, Tartaglia, Marco, De Maria, Ruggero, and Zeuner, Ann
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- 2019
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5. The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells
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Matteoni, Silvia, Abbruzzese, Claudia, Matarrese, Paola, De Luca, Gabriele, Mileo, Anna M., Miccadei, Stefania, Schenone, Silvia, Musumeci, Francesca, Haas, Tobias L., Sette, Giovanni, Carapella, Carmine M., Amato, Rosario, Perrotti, Nicola, Signore, Michele, and Paggi, Marco G.
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- 2019
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6. Lung Cancer Organoids: The Rough Path to Personalized Medicine
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Rossi, Rachele, primary, De Angelis, Maria Laura, additional, Xhelili, Eljona, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, De Maria, Ruggero, additional, Cesta Incani, Ursula, additional, Francescangeli, Federica, additional, and Zeuner, Ann, additional
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- 2022
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7. Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models
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Del Curatolo, Anais, Conciatori, Fabiana, Cesta Incani, Ursula, Bazzichetto, Chiara, Falcone, Italia, Corbo, Vincenzo, D’Agosto, Sabrina, Eramo, Adriana, Sette, Giovanni, Sperduti, Isabella, De Luca, Teresa, Marabese, Mirko, Shirasawa, Senji, De Maria, Ruggero, Scarpa, Aldo, Broggini, Massimo, Del Bufalo, Donatella, Cognetti, Francesco, Milella, Michele, and Ciuffreda, Ludovica
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- 2018
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8. Lung Cancer Organoids: The Rough Path to Personalized Medicine
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Rossi, Rachele, De Angelis, Maria Laura, Xhelili, Eljona, Sette, Giovanni, Eramo, Adriana, De Maria Marchiano, Ruggero, Cesta Incani, Ursula, Francescangeli, Federica, Zeuner, Ann, De Maria, Ruggero (ORCID:0000-0003-2255-0583), Rossi, Rachele, De Angelis, Maria Laura, Xhelili, Eljona, Sette, Giovanni, Eramo, Adriana, De Maria Marchiano, Ruggero, Cesta Incani, Ursula, Francescangeli, Federica, Zeuner, Ann, and De Maria, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Simple Summary Lung cancer is very difficult to cure, especially when it has spread to other parts of the body. One of the main reasons that delay the identification of effective therapies is the complexity of lung cancer cells, which can be very different among individual patients. Organoids are small aggregates of tumor cells that are generated from lung tumors and used in cancer research laboratories to study the features of tumor cells. Organoids have unique properties, as they reproduce many characteristics of the tumor derived from each specific patient. Due to their capacity to reproduce individual tumor features in the laboratory setting, organoids are an excellent system to study lung cancer and to identify functional therapies. This review summarizes the challenges encountered by researchers in the field of lung cancer organoids and describes how the advances in organoid technology may allow the future development of individualized therapies for lung cancer patients. Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10-20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further ad
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- 2022
9. CRIPTO Is a Marker of Chemotherapy-Induced Stem Cell Expansion in Non-Small Cell Lung Cancer
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Francescangeli, Federica, primary, De Angelis, Maria Laura, additional, Rossi, Rachele, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, Boe, Alessandra, additional, Guardiola, Ombretta, additional, Tang, Tao, additional, Yu, Shi-Cang, additional, Minchiotti, Gabriella, additional, and Zeuner, Ann, additional
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- 2022
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10. Ex Vivo Irradiation of Lung Cancer Stem Cells Identifies the Lowest Therapeutic Dose Needed for Tumor Growth Arrest and Mass Reduction In Vivo
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Puglisi, Caterina, primary, Giuffrida, Raffaella, additional, Borzì, Giuseppina, additional, Illari, Salvatore, additional, Caronia, Francesco Paolo, additional, Di Mattia, Paolo, additional, Colarossi, Cristina, additional, Ferini, Gianluca, additional, Martorana, Emanuele, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, Lorico, Aurelio, additional, Di Grazia, Alfio, additional, and Forte, Stefano, additional
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- 2022
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11. Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells
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Sette, Giovanni, primary, Lo Cicero, Stefania, additional, Blaconà, Giovanna, additional, Pierandrei, Silvia, additional, Bruno, Sabina Maria, additional, Salvati, Valentina, additional, Castelli, Germana, additional, Falchi, Mario, additional, Fabrizzi, Benedetta, additional, Cimino, Giuseppe, additional, De Maria, Ruggero, additional, Biffoni, Mauro, additional, Eramo, Adriana, additional, and Lucarelli, Marco, additional
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- 2021
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12. Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells
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Tabolacci, Claudio, Cordella, Martina, Turcano, Lorenzo, Rossi, Stefania, Lentini, Alessandro, Mariotti, Sabrina, Nisini, Roberto, Sette, Giovanni, Eramo, Adriana, Piredda, Lucia, De Maria, Ruggero, Facchiano, Francesco, and Beninati, Simone
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- 2015
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13. Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells
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Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., De Maria R. (ORCID:0000-0003-2255-0583), Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Question Cystic fibrosis (CF) is due to pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent improvements have enabled pharmacological therapy aiming at restoring mutated CFTR expression and function. CFTR "modulators"have revolutionised the CF therapeutic landscape, particularly the last approved, Trikafta. This drug combination is indicated by the United States Food and Drug Administration and very recently by the European Medicines Agency for genotypes carrying at least one copy of CFTR with the F508del pathogenic variant. However, several genotypes are not yet eligible for Trikafta treatment. Materials/patients and methods We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients. This approach, coupled to the development of AESC-derived personalised disease models, as organoids and air-liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological testing. Results and answer to the question We fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, which allowed the evaluation of the efficacy of clinically available modulators in restoring CFTR maturation and function of each patientderived "avatar"(theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. In addition, Trikafta showed its efficacy on three rare genotypes previously not eligible for treatment with modulators, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were obtained.
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- 2021
14. The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms
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Ciuffreda, Ludovica, Di Sanza, Cristina, Cesta Incani, Ursula, Eramo, Adriana, Desideri, Marianna, Biagioni, Francesca, Passeri, Daniela, Falcone, Italia, Sette, Giovanni, Bergamo, Paola, Anichini, Andrea, Sabapathy, Kanaga, McCubrey, James A., Ricciardi, Maria Rosaria, Tafuri, Agostino, Blandino, Giovanni, Orlandi, Augusto, De Maria, Ruggero, Cognetti, Francesco, Del Bufalo, Donatella, and Milella, Michele
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- 2012
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15. Abstracts from the 23rd Italian congress of Cystic Fibrosis and the 13th National congress of Cystic Fibrosis Italian Society
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Bevivino, Annamaria, Coiana, Alessandra, Fogazzi, Annalisa, Timelli, Fabiana, Signorini, Sandra, Lucarelli, Marco, Morelli, Patrizia, Padoan, Rita, Giordani, Barbara, Amato, Annalisa, Majo, Fabio, Ferrari, Gianluca, Quattrucci, Serena, Minicucci, Laura, Floridia, Giovanna, Fornaro, Gianna Puppo, Taruscio, Domenica, Salvatore, Marco, Seia, Manuela, Pierandrei, Silvia, Blaconà, Giovanna, Salvati, Valentina, Sette, Giovanni, Cimino, Giuseppe, Sangiuolo, Federica, Eramo, Adriana, Collura, Mirella, Parisi, Elisa, Ferlisi, Annalisa, Traverso, Gabriella, Bertolino, Marcella, Termini, Lisa, Orlando, Maria A., Di Girgenti, Caterina, Pavone, Valeria, Calamia, Maria A., Silvestro, Maria G., Piparo, Caterina Lo, Ficili, Francesca, Colombo, Carla, Tullis, Elizabeth, Davies, Jane C., Mckee, Charlotte, Desouza, Cynthia, Waltz, David, Savage, Jessica, Fisher, Marc, Shilling, Rebecca, Moskowitz, Sam, Robertson, Sarah, Tian, Simon, Taylor-Cousar, Jennifer L., Rowe, Steven M., Beccia, Elisa, Carbone, Annalucia, Favia, Maria, Castellani, Stefano, Angiolillo, Antonella, Casavola, Valeria, Conese, Massimo, Cesana, Bruno M., Falchetti, Diego, Battistini, Fiorella, Bignamini, Elisabetta, Braggion, Cesare, Cirilli, Natalia, Lucanto, Maria C., Lucidi, Vincenzina, Manca, Antonio, Raia, Valeria, Rotolo, Novella, Salvatore, Donatello, Volpi, Sonia, Nazzari, Erica, Guarise, Riccardo, Mileto, Palmiro, Garbarino, Francesca, Alicandro, Gianfranco, Battezzati, Alberto, Di Lullo, Antonella M., Comegna, Marika, Amato, Felice, Iacotucci, Paola, Carnovale, Vincenzo, Cantone, Elena, Iengo, Maurizio, Castaldo, Giuseppe, Orlando, Claudio, Casale, Alida, Sepe, Angela, De Gregorio, Fabiola, De Matteo, Antonia, Castaldo, Alice, Cimbalo, Chiara, Tosco, Antonella, Savi, Daniela, Mordenti, Michela, Bonci, Enea, Troiani, Patrizia, D’Alù, Viviana, Rossi, Paolo, Varchetta, Monica, Perelli, Tamara, Bertasi, Serenella, Palange, Paolo, Tardino, Lucia, Parisi, Giuseppe F., Portale, Anna, Franzonello, Chiara, Papale, Maria, Leonardi, Salvatore, Pennisi, Francesca, Bruno, Sabina M., Licciardello, Giulia, Ferraguti, Giampiero, Sterrantino, Manuela, Testino, Giancarlo, Buzzetti, Roberto, Surace, Cecilia, Sofia, Valentina M., Ullmann, Nicola, Novelli, Antonio, Angioni, Adriano, Liguori, Renato, Manzoni, Francesca, Di Palma, Chiara, Maietta, Sabrina, Zarrilli, Federica, Terlizzi, Vito, Alghisi, Federico, Tuccio, Giuseppe, Tradati, Valentina, di Stefano, Eliana, Dato, Patrizia, Sciarrabone, Maria G., Fondacaro, Carmela, Cresta, Federico, Baglioni, Valentina, Garuti, Silvia, Buffoni, Isabella, Landi, Francesca, Casciaro, Rosaria, Girelli, Daniela, Teri, Antonio, Sottotetti, Samantha, Biffi, Arianna, Vignati, Chiara, D’Accico, Monica, Maraschini, Anna, Arghittu, Milena, Pizzamiglio, Giovanna, Cariani, Elisa, Dolce, Daniela, Ravenni, Novella, Campana, Silvia, Camera, Erica, Castellani, Carlo, Taccetti, Giovanni, Calderone, Eleonora, Bandettini, Roberto, Innocenti, Chiara Degli, Castellani, Chiara, Masi, Eleonora, Cavicchi, Maria Chiara, Ferrari, Beatrice, Pezzotta, Ramona, Poli, Piercarlo, Messali, Serena, Timpano, Silvana, Scaltriti, Erika, Pongolini, Stefano, Fiorentini, Simona, Bresci, Silvia, Corsi, Lorenzo, Borchi, Beatrice, Cavallo, Annalisa, Bartalesi, Filippo, Pistolesi, Massimo, Bartoloni, Alessandro, Arcoleo, Federica, Pensabene, Tiziana, Bacci, Giovanni, Armanini, Federica, Fiscarelli, Ersilia V., Segata, Nicola, Mengoni, Alessio, Di Toppa, Maria V., Popa, Nicoleta, Felicetti, Francesco, Graziano, Sonia, Ciprandi, Riccardo, Pescini, Rita, Graffigna, Guendalina, Barello, Serena, Catastini, Paola, De Masi, Salvatore, Braggion, C., Guarnuto, Lucia, Di Liberti, Emanuela, Patti, Valentina, Castellazzi, Massimo Luca, Daccò, Valeria, Claut, Laura, Giuliari, Matteo, Vicentini, Luana, Tilotta, Fausto, Paciaroni, Antonella, Sala, Sabino Della, Guerzoni, Cristina, Andreatta, Elisa, Dinnella, Grazia, Granata, Orazia M., Aronica, Tommaso S., Crapisi, Mimì, Fogazza, Donatella, Alessi, Luca, Mulè, Flavia, Vitaliti, Marcello, Maresi, Mariarosaria, Catzola, Andrea, Salvadori, Laura, Colangelo, Carmela, Marsicovetere, Giovanni, D’Andria, Michele, Passarella, Domenica, Genovese, Carmela, Orlando, Mari A., Barrale, Stefania, Bonaccorso, Maria R., and D’Arpa, Annalisa
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lcsh:RJ1-570 ,lcsh:Pediatrics ,Meeting Abstracts - Published
- 2018
16. LC-HRMS/MS for the simultaneous determination of four allergens in fish and swine food products
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Stella, Roberto, primary, Sette, Giovanni, additional, Moressa, Alessandra, additional, Gallina, Albino, additional, Aloisi, Anna Maria, additional, Angeletti, Roberto, additional, and Biancotto, Giancarlo, additional
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- 2020
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17. Evaluation and quantification of antimicrobial residues and antimicrobial resistance genes in two Italian swine farms
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Petrin, Sara, primary, Patuzzi, Ilaria, additional, Di Cesare, Andrea, additional, Tiengo, Alessia, additional, Sette, Giovanni, additional, Biancotto, Giancarlo, additional, Corno, Gianluca, additional, Drigo, Michele, additional, Losasso, Carmen, additional, and Cibin, Veronica, additional
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- 2019
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18. Additional file 2: of The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells
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Matteoni, Silvia, Abbruzzese, Claudia, Matarrese, Paola, Luca, Gabriele De, Mileo, Anna, Miccadei, Stefania, Schenone, Silvia, Musumeci, Francesca, Haas, Tobias, Sette, Giovanni, Carapella, Carmine, Amato, Rosario, Perrotti, Nicola, Signore, Michele, and Paggi, Marco
- Abstract
Figure S1. Additional RPPA endpoints. (PDF 89474 kb)
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- 2019
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19. Additional file 1: of A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells
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Orienti, Isabella, Salvati, Valentina, Sette, Giovanni, Zucchetti, Massimo, Bongiorno-Borbone, Lucilla, Peschiaroli, Angelo, Zolla, Lello, Francescangeli, Federica, Ferrari, Mariella, Matteo, Cristina, Bello, Ezia, Virgilio, Antonio Di, Falchi, Mario, Angelis, Maria De, Baiocchi, Marta, Melino, Gerry, Maria, Ruggero De, Zeuner, Ann, and Eramo, Adriana
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carbohydrates (lipids) - Abstract
Figure S1. Metabolites plasma concentrations (MPR and oxo-4-HPR) determined in mice after single oral treatment of 4 doses of Bio-nFeR: 10, 50, 100 and 200 mg/Kg. The analysis was performed after 0, 24, 48 h. Figure S2. Evaluation of the 50% inhibitory concentration (IC50) of BionFeR and NCI-FeR formulation was done on a representative lung cancer stem cell line (LCSC). The cells were exposed to the indicated drug doses (0–30 μM) and cell viability was evaluated by CellTiter-Glo after 72 h. Figure S3. A) Sphingomyelin-Ceramide (SM-CER) and Sphingomyelin- Dihydro-Ceramide (SM-DH-CER) content in lung (LC), melanoma (MEL) and colon (CRC) tumors treated with Bio-nFeR at single 100–150 mg/Kg administration were quantified through Ultra High Performance Liquid Chromatography (UHPLC), normalized to control and plotted as fold change. B) Quantification of Glucosyl-Ceramide (GLC-CER) and Glucosyl-Dihydro-Ceramide (GLC-DH-CER) in the same samples as in A, normalized to control and plotted as fold change. Figure S4. Cancer stem cell marker expression in CSC-culture conditions and in CSC-derived xenografts. A) Flow cytometry analysis of Aldefluor in (left panels) and CD44v6 (middle and right panels) in the indicated CSC and xenograft samples. B) Immunoblot analysis of CSC antigens c-Kit and SOX-2 in the indicated control (−) or BionFeR treated (+) melanoma xenografts. β-actin blot was used for equal loading control. Figure S5. Growth curves of lung CSC-derived xenografts in control mice or mice treated with Bio-nFeR or NCI-FeR at 100 mg/kg dose for the indicated times. Mean ± standard error is shown. *P
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- 2019
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20. Additional file 1: of The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells
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Matteoni, Silvia, Abbruzzese, Claudia, Matarrese, Paola, Luca, Gabriele De, Mileo, Anna, Miccadei, Stefania, Schenone, Silvia, Musumeci, Francesca, Haas, Tobias, Sette, Giovanni, Carapella, Carmine, Amato, Rosario, Perrotti, Nicola, Signore, Michele, and Paggi, Marco
- Abstract
Table S1. Complete list of antibodies used for RPPA analysis and their main related information. (PDF 26 kb)
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- 2019
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21. Additional file 4: of The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells
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Matteoni, Silvia, Abbruzzese, Claudia, Matarrese, Paola, Luca, Gabriele De, Mileo, Anna, Miccadei, Stefania, Schenone, Silvia, Musumeci, Francesca, Haas, Tobias, Sette, Giovanni, Carapella, Carmine, Amato, Rosario, Perrotti, Nicola, Signore, Michele, and Paggi, Marco
- Abstract
Figure S2. Clonogenic Assay. (PDF 440 kb)
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- 2019
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22. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells
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Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., De Maria R. (ORCID:0000-0003-2255-0583), Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
- Published
- 2019
23. The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells
- Author
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Matteoni, S., Abbruzzese, C., Matarrese, P., De Luca, G., Mileo, A. M., Miccadei, S., Schenone, S., Musumeci, F., Haas, Tobias Longin, Sette, Giovanni, Carapella, C. M., Amato, R., Perrotti, N., Signore, M., Paggi, M. G., Haas T. L. (ORCID:0000-0003-2336-0263), Sette G., Matteoni, S., Abbruzzese, C., Matarrese, P., De Luca, G., Mileo, A. M., Miccadei, S., Schenone, S., Musumeci, F., Haas, Tobias Longin, Sette, Giovanni, Carapella, C. M., Amato, R., Perrotti, N., Signore, M., Paggi, M. G., Haas T. L. (ORCID:0000-0003-2336-0263), and Sette G.
- Abstract
Background: Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM. Methods: We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades. Results: SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with autophagy inhibitors. Indeed, the association of SI113 with an autophagy inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres. Conclusions: RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy.
- Published
- 2019
24. Conditionally reprogrammed cells (CRC) methodology does not allow the in vitro expansion of patient-derived primary and metastatic lung cancer cells
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Sette, Giovanni, Salvati, Valentina, Ilenia, Giordani, Emanuela, Pillozzi, Denise, Quacquarini, Enrico, Duranti, Francesca De Nicola, Matteo, Pallocca, Maurizio, Fanciulli, Mario, Falchi, Pallini, Roberto, De Maria Marchiano, Ruggero, and Adriana, Eramo
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Male ,conditionally reprogrammed cells (crc) ,epithelial respiratory cells ,lung cancer ,stem cells ,oncology ,cancer research ,Lung Neoplasms ,Biopsy ,Breast Neoplasms ,Mice ,Settore MED/04 - PATOLOGIA GENERALE ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Cellular Reprogramming Techniques ,Aged ,Settore MED/06 - ONCOLOGIA MEDICA ,Epithelial Cells ,Middle Aged ,Phenotype ,Lung cancer, stem cells, conditionally reprogrammed cells (CRC), epithelial respiratory cells ,Colonic Neoplasms ,Mutation ,Female ,Lung cancer ,Neoplasm Transplantation ,conditionally reprogrammed cells (CRC) - Abstract
Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for non-small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells from either tumor or non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor-derived CRC cultures are composed of (non-tumoral) airway basal cells.
- Published
- 2018
25. Natural compound Tetrocarcin-A downregulates Junctional Adhesion Molecule-A in conjunction with HER2 and inhibitor of apoptosis proteins and inhibits tumor cell growth
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Vellanki, Sri HariKrishna, primary, Cruz, Rodrigo G.B., additional, Jahns, Hanne, additional, Hudson, Lance, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, and Hopkins, Ann M., additional
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- 2019
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26. Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma
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Santoro Antonio, Mari Emanuela, Sale Patrizio, Eramo Adriana, Sette Giovanni, De Santis Elena, Pellegrini Laura, Frati Alessandro, Di Vito Maura, Tafani Marco, Raco Antonino, Salvati Maurizio, De Maria Ruggero, and Russo Matteo A
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Adaptation to hypoxia and consequent pro-inflammatory gene expression of prostate and breast carcinomas have been implicated in the progression toward cancer malignant phenotype. Only partial data are available for the human tumor glioblastoma multiforme (GBM). The aim of our study was to analyze the hypoxic and pro-inflammatory microenvironment in GBMs and to demonstrate that in a stem/progenitor cell line derived from human glioblastoma (GBM-SCs), hypoxia activates a coordinated inflammatory response, evidencing an invasive and migratory phenotype. Methods From each of 10 human solid glioblastomas, clinically and histopathologically characterized, we obtained three surgical samples taken from the center and the periphery of the tumor, and from adjacent host normal tissue. Molecular and morphological analyses were carried out using quantitative real-time PCR and western blot (WB). GBM stem and differentiated cells were incubated under hypoxic conditions and analyzed for pro-inflammatory gene expression and for invasive/migratory behavior. Results A panel of selected representative pro-inflammatory genes (RAGE and P2X7R, COX2, NOS2 and, PTX3) were analyzed, comparing tumor, peritumor and host normal tissues. Tumors containing leukocyte infiltrates (as assessed using CD45 immunohistochemistry) were excluded. Selected genes were overexpressed in the central regions of the tumors (i.e. in the more hypoxic areas), less expressed in peripheral regions, and poorly expressed or absent in adjacent normal host tissues. Western blot analysis confirmed that the corresponding pro-inflammatory proteins were also differently expressed. Hypoxic stem cell lines showed a clear time-dependent activation of the entire panel of pro-inflammatory genes as compared to differentiated tumor cells. Biological assays showed that invasive and migratory behavior was strengthened by hypoxia only in GBM stem cells. Conclusions In human solid glioblastoma we have observed a coordinated overexpression of a panel of pro-inflammatory genes as compared to host normal tissue. We have also evidenced a similar pattern of overexpressed genes in GBM-SCs after hypoxic treatment, showing also a gain of invasive and migratory function that was lost when these stem cells differentiated. We suggest that, as has been previously described for prostatic and mammary carcinoma, in human glioblastoma acquisition of a proinflammatory phenotype may be relevant for malignant progression.
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- 2011
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27. Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models
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Del Curatolo, Anai, Conciatori, Fabiana, Cesta Incani, Ursula, Bazzichetto, Chiara, Falcone, Italia, Corbo, Vincenzo, D'Agosto, Sabrina, Eramo, Adriana, Sette, Giovanni, Sperduti, Isabella, De Luca, Teresa, Marabese, Mirko, Shirasawa, Senji, De Maria Marchiano, Ruggero, Scarpa, Aldo, Broggini, Massimo, Del Bufalo, Donatella, Cognetti, Francesco, Milella, Michele, Ciuffreda, Ludovica, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Del Curatolo, Anai, Conciatori, Fabiana, Cesta Incani, Ursula, Bazzichetto, Chiara, Falcone, Italia, Corbo, Vincenzo, D'Agosto, Sabrina, Eramo, Adriana, Sette, Giovanni, Sperduti, Isabella, De Luca, Teresa, Marabese, Mirko, Shirasawa, Senji, De Maria Marchiano, Ruggero, Scarpa, Aldo, Broggini, Massimo, Del Bufalo, Donatella, Cognetti, Francesco, Milella, Michele, Ciuffreda, Ludovica, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Background: Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade. Methods: We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables. Results: Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade. Conclusions: Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting.
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- 2018
28. Abstract 2670: Natural compound tetrocarcin-A downregulates junctional adhesion molecule-A in conjunction with erα, her2 and inhibitor of apoptosis proteins and inhibits tumor cell growth
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Vellanki, Sri Harikrishna, primary, Hudson, Lance, additional, Jahns, Hanne, additional, Cruz, Rodrigo G.B., additional, Sette, Giovanni, additional, Eramo, Adriana, additional, and Hopkins, Ann M., additional
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- 2018
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29. Conditionally reprogrammed cells (CRC) methodology does not allow thein vitroexpansion of patient-derived primary and metastatic lung cancer cells
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Sette, Giovanni, primary, Salvati, Valentina, additional, Giordani, Ilenia, additional, Pilozzi, Emanuela, additional, Quacquarini, Denise, additional, Duranti, Enrico, additional, De Nicola, Francesca, additional, Pallocca, Matteo, additional, Fanciulli, Maurizio, additional, Falchi, Mario, additional, Pallini, Roberto, additional, De Maria, Ruggero, additional, and Eramo, Adriana, additional
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- 2018
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30. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
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Milella, Michele, Falcone, Italia, Conciatori, Fabiana, Matteoni, Silvia, Sacconi, Andrea, De Luca, Teresa, Bazzichetto, Chiara, Corbo, Vincenzo, Simbolo, Michele, Sperduti, Isabella, Benfante, Antonina, Del Curatolo, Anai, Cesta Incani, Ursula, Malusa, Federico, Eramo, Adriana, Sette, Giovanni, Scarpa, Aldo, Konopleva, Marina, Andreeff, Michael, Mccubrey, James Andrew, Blandino, Giovanni, Todaro, Matilde, Stassi, Giorgio, De Maria Marchiano, Ruggero, Cognetti, Francesco, Del Bufalo, Donatella, Ciuffreda, Ludovica, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Milella, Michele, Falcone, Italia, Conciatori, Fabiana, Matteoni, Silvia, Sacconi, Andrea, De Luca, Teresa, Bazzichetto, Chiara, Corbo, Vincenzo, Simbolo, Michele, Sperduti, Isabella, Benfante, Antonina, Del Curatolo, Anai, Cesta Incani, Ursula, Malusa, Federico, Eramo, Adriana, Sette, Giovanni, Scarpa, Aldo, Konopleva, Marina, Andreeff, Michael, Mccubrey, James Andrew, Blandino, Giovanni, Todaro, Matilde, Stassi, Giorgio, De Maria Marchiano, Ruggero, Cognetti, Francesco, Del Bufalo, Donatella, Ciuffreda, Ludovica, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.
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- 2017
31. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
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Milella, M, Falcone, I, Conciatori, F, Matteoni, S, Sacconi, A, De Luca, T, Bazzichetto, C, Corbo, V, Simbolo, M, Sperduti, I, Benfante, A, Del Curatolo, A, Cesta Incani, U, Malusa, F, Eramo, A, Sette, Giovanni, Scarpa, A, Konopleva, M, Andreeff, M, Mccubrey, Ja, Blandino, G, Todaro, M, Stassi, G, De Maria Marchiano, Ruggero, Cognetti, F, Del Bufalo, D, Ciuffreda, L., Sette G, De Maria Marchiano R (ORCID:0000-0003-2255-0583), Milella, M, Falcone, I, Conciatori, F, Matteoni, S, Sacconi, A, De Luca, T, Bazzichetto, C, Corbo, V, Simbolo, M, Sperduti, I, Benfante, A, Del Curatolo, A, Cesta Incani, U, Malusa, F, Eramo, A, Sette, Giovanni, Scarpa, A, Konopleva, M, Andreeff, M, Mccubrey, Ja, Blandino, G, Todaro, M, Stassi, G, De Maria Marchiano, Ruggero, Cognetti, F, Del Bufalo, D, Ciuffreda, L., Sette G, and De Maria Marchiano R (ORCID:0000-0003-2255-0583)
- Abstract
Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status con rmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic pro le modi cation(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identi ed JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of bene t from combined therapeutic strategies.
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- 2017
32. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
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Milella, Michele, primary, Falcone, Italia, additional, Conciatori, Fabiana, additional, Matteoni, Silvia, additional, Sacconi, Andrea, additional, De Luca, Teresa, additional, Bazzichetto, Chiara, additional, Corbo, Vincenzo, additional, Simbolo, Michele, additional, Sperduti, Isabella, additional, Benfante, Antonina, additional, Del Curatolo, Anais, additional, Cesta Incani, Ursula, additional, Malusa, Federico, additional, Eramo, Adriana, additional, Sette, Giovanni, additional, Scarpa, Aldo, additional, Konopleva, Marina, additional, Andreeff, Michael, additional, McCubrey, James Andrew, additional, Blandino, Giovanni, additional, Todaro, Matilde, additional, Stassi, Giorgio, additional, De Maria, Ruggero, additional, Cognetti, Francesco, additional, Del Bufalo, Donatella, additional, and Ciuffreda, Ludovica, additional
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- 2017
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33. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells
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Di Martile, Marta, Desideri, Marianna, De Luca, Teresa, Gabellini, Chiara, Buglioni, Simonetta, Eramo, Adriana, Sette, Giovanni, Milella, Michele, Rotili, Dante, Mai, Antonello, Carradori, Simone, Secci, Daniela, De Maria Marchiano, Ruggero, Del Bufalo, Donatella, Trisciuoglio, Daniela, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Di Martile, Marta, Desideri, Marianna, De Luca, Teresa, Gabellini, Chiara, Buglioni, Simonetta, Eramo, Adriana, Sette, Giovanni, Milella, Michele, Rotili, Dante, Mai, Antonello, Carradori, Simone, Secci, Daniela, De Maria Marchiano, Ruggero, Del Bufalo, Donatella, Trisciuoglio, Daniela, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.
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- 2016
34. Abstract 2484: Non-canonical Hedgehog/Gli1 signaling drives lung adenocarcinoma stem cells survival and its targeting inhibits CSC-derived tumors
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Po, Agnese, primary, Silvano, Marianna, additional, Miele, Evelina, additional, Eramo, Adriana, additional, Todaro, Matilde, additional, Capalbo, Carlo, additional, Salvati, Valentina, additional, Sette, Giovanni, additional, Cucchi, Danilo, additional, Besharat, Zein M., additional, Canettieri, Gianluca, additional, Di Marcotullio, Lucia, additional, Screpanti, Isabella, additional, Stassi, Giorgio, additional, De Maria, Ruggero, additional, Zeuner, Ann, additional, De Smaele, Enrico, additional, and Ferretti, Elisabetta, additional
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- 2016
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35. Wharton's jelly mesenchymal stromal cells have contrasting effects on proliferation and phenotype of cancer stem cells from different subtypes of lung cancer
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Vulcano, Francesca, primary, Milazzo, Luisa, additional, Ciccarelli, Carmela, additional, Eramo, Adriana, additional, Sette, Giovanni, additional, Mauro, Annunziata, additional, Macioce, Giampiero, additional, Martinelli, Andrea, additional, La Torre, Renato, additional, Casalbore, Patrizia, additional, Hassan, Hamisa Jane, additional, and Giampaolo, Adele, additional
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- 2016
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36. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells
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Di Martile, Marta, primary, Desideri, Marianna, additional, De Luca, Teresa, additional, Gabellini, Chiara, additional, Buglioni, Simonetta, additional, Eramo, Adriana, additional, Sette, Giovanni, additional, Milella, Michele, additional, Rotili, Dante, additional, Mai, Antonello, additional, Carradori, Simone, additional, Secci, Daniela, additional, De Maria, Ruggero, additional, Del Bufalo, Donatella, additional, and Trisciuoglio, Daniela, additional
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- 2016
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37. Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer
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Sette, Giovanni, Salvati, Valentina, Mottolese, M., Visca, P., Gallo, E., Fecchi, K., Pilozzi, E., Duranti, E., Policicchio, E., Tartaglia, Marco, Milella, M., De Maria Marchiano, Ruggero, Eramo, A., Sette, G., Salvati, V., Tartaglia, M., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Sette, Giovanni, Salvati, Valentina, Mottolese, M., Visca, P., Gallo, E., Fecchi, K., Pilozzi, E., Duranti, E., Policicchio, E., Tartaglia, Marco, Milella, M., De Maria Marchiano, Ruggero, Eramo, A., Sette, G., Salvati, V., Tartaglia, M., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EG
- Published
- 2015
38. Conditionally reprogrammed cells (CRC) methodology does not allow the <italic>in vitro</italic> expansion of patient‐derived primary and metastatic lung cancer cells.
- Author
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Sette, Giovanni, Salvati, Valentina, Giordani, Ilenia, Pilozzi, Emanuela, Quacquarini, Denise, Duranti, Enrico, De Nicola, Francesca, Pallocca, Matteo, Fanciulli, Maurizio, Falchi, Mario, Pallini, Roberto, De Maria, Ruggero, and Eramo, Adriana
- Abstract
Availability of tumor and non‐tumor patient‐derived models would promote the development of more effective therapeutics for non‐small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient‐derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non‐tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non‐malignant tissues with extraordinary high efficiency. Tumor cells were tracked
in vitro through tumorigenicity assay, monitoring of tumor‐specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies‐derived cultures rapidly lost patient‐specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient‐derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non‐malignant lung epithelial stem cells from either tumor or non‐tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor‐derived CRC cultures are composed of (non‐tumoral) airway basal cells. [ABSTRACT FROM AUTHOR]- Published
- 2018
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39. L’inibizione di EGFR abroga la chemioresistenza delle cellule di Leiomiosarcoma attraverso l’inattivazione di segnali di sopravvivenza e riduzione del potenziale di staminalità
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Sette, Giovanni and ERAMO, ADRIANA
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Settori Disciplinari MIUR::Scienze mediche ,Scienze mediche [Settori Disciplinari MIUR] ,IRESSA ,Side population ,leiomiosarcoma ,EGFR ,Settori Disciplinari MIUR::Scienze biologiche ,chemioresistenza ,Scienze biologiche [Settori Disciplinari MIUR] ,cellule staminali tumorali - Abstract
Cellule tumorali che mostrano un fenotipo e posseggono proprietà di cellule staminali, sono definite cellule staminali tumorali (CSC). Esse sono state identificate in diversi tumori solidi e si presume che siano le responsabili della crescita del tumore, della chemio-resistenza, della formazione di metastasi e delle recidive osservate nei pazienti e. Una sottopopolazione di cellule con un più alto potenziale staminale, è stata già identificata all’interno dei sarcomi. Queste cellule presentano un elevato potenziale tumorigenico, sono chemioresistenti, esprimono marcatori di tipo embrionale e possiedono un fenotipo di side population (SP). Il leiomiosarcoma (LMS) è un sarcoma dei tessuti molli che origina presumibilmente da cellule indifferenziate di origine mesenchimale, le Cellule Staminali Mesenchimali (MSC). Le frequenti ricadute e la chemioresistenza osservata in pazienti affetti da leiomiosarcoma potrebbe derivare dalla mancata efficacia dei farmaci, attualmente utilizzati in clinica, sulla sottopopolazione di CSC. Ne emerge che terapie innovative che abbiano come bersaglio principale le cellule staminali tumorali (CSC), potrebbero migliorare notevolmente la prognosi dei pazienti affetti da LMS. In questo lavoro abbiamo espanso in vitro cellule staminali di LMS da biopsia asportata da paziente con lo scopo di contrastare questa neoplasia colpendo la popolazione più tumorigenica. CSC di LMS sono state espanse in vitro sia come “ sferoidi” che come “monostrato di cellule aderenti” ottenuto in condizioni utilizzate per coltivare le MSC. Esse presentano un fenotipo di tipo mesenchimale indifferenziato, hanno un’alta percentuale di cellule con fenotipo SP, un’elevata capacità di espellere farmaci, un illimitato potenziale proliferativo e di auto autoreplicazione; inoltre sono in grado di differenziare nei diversi lineage di tipo mesenchimale. Le CSC di LMS sono chemioresistenti, altamente tumorigeniche, e riproducono fedelmente il tumore del paziente in topi immunodeficenti. Esse presentano attivazione del pathway di EGFR/AKT/MAPK, suggerendo la possibilità di inibire la loro chemioresistenza mediante il blocco di questa via di segnale. Il trattamento combinato con IRESSA più Vincristina determina l’inattivazione della via del segnale di EGFR, riduce la SP, esercita un’elevata citotossicità in vitro e una forte attività antitumorale in xenografts generati dalle CSC di LMS, colpendo sia le cellule staminali sia differenziate. In conclusione, il trattamento con l’inibitore di EGFR in combinazione con la vincristina determina un marcato effetto antitumorale sia in vitro che in vivo contro le cellule di LMS, fornendo una possibile terapia antitumorale per pazienti affetti da LMS. This work was supported by the Italian Association for Cancer Research and the Italian Health Ministry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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- 2012
40. Chemotherapy resistance of glioblastoma stem cells [2]
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Eramo, A., Ricci-Vitiani, L., Zeuner, A., Pallini, Roberto, Lotti, F., Sette, Giovanni, Pilozzi, E., Larocca, Luigi Maria, Peschle, C., and De Maria Marchiano, Ruggero
- Subjects
Time Factors ,Cultured ,Brain Neoplasms ,Nude ,Animals ,Antineoplastic Agents ,Apoptosis ,Cisplatin ,Doxorubicin ,Etoposide ,Glioblastoma ,Humans ,Jurkat Cells ,Mice ,Mice, Nude ,Neoplastic Stem Cells ,Tumor Cells, Cultured ,Xenograft Model Antitumor Assays ,Drug Resistance, Multiple ,Drug Resistance, Neoplasm ,Cell Biology ,Drug Resistance ,Tumor Cells ,Settore MED/04 - PATOLOGIA GENERALE ,Neoplasm ,Multiple - Published
- 2006
41. Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts
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Sette, Giovanni, Fecchi, Katia, Salvati, Valentina, Lotti, Fiorenza, Pilozzi, Emanuela, Duranti, Enrico, Biffoni, Mauro, Pagliuca, Alfredo, Martinetti, Daniela, Memeo, Lorenzo, Milella, Michele, De Maria Marchiano, Ruggero, Eramo, Adriana, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Sette, Giovanni, Fecchi, Katia, Salvati, Valentina, Lotti, Fiorenza, Pilozzi, Emanuela, Duranti, Enrico, Biffoni, Mauro, Pagliuca, Alfredo, Martinetti, Daniela, Memeo, Lorenzo, Milella, Michele, De Maria Marchiano, Ruggero, Eramo, Adriana, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets. © 2013 Sette et al.; licensee BioMed Central Ltd.
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- 2013
42. Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts
- Author
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Sette, Giovanni, primary, Fecchi, Katia, additional, Salvati, Valentina, additional, Lotti, Fiorenza, additional, Pilozzi, Emanuela, additional, Duranti, Enrico, additional, Biffoni, Mauro, additional, Pagliuca, Alfredo, additional, Martinetti, Daniela, additional, Memeo, Lorenzo, additional, Milella, Michele, additional, De Maria, Ruggero, additional, and Eramo, Adriana, additional
- Published
- 2013
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43. EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential
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Sette, Giovanni, Salvati, Valentina, Memeo, Lorenzo, Fecchi, Katia, Colarossi, Cristina, Di Matteo, Paola, Signore, Michele, Biffoni, Mauro, D'Andrea, Vito, de Antoni, Enrico, Canzonieri, Vincenzo, De Maria Marchiano, Ruggero, Eramo, Adriana, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Sette, Giovanni, Salvati, Valentina, Memeo, Lorenzo, Fecchi, Katia, Colarossi, Cristina, Di Matteo, Paola, Signore, Michele, Biffoni, Mauro, D'Andrea, Vito, de Antoni, Enrico, Canzonieri, Vincenzo, De Maria Marchiano, Ruggero, Eramo, Adriana, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Background: Tumor cells with stem-like phenotype and properties, known as cancer stem cells (CSC), have been identified in most solid tumors and are presumed to be responsible for driving tumor initiation, chemoresistance, relapse, or metastasis. A subpopulation of cells with increased stem-like potential has also been identified within sarcomas. These cells are endowed with increased tumorigenic potential, chemoresistance, expression of embryonic markers, and side population(SP) phenotype. Leiomyosarcomas (LMS) are soft tissue sarcomas presumably arising from undifferentiated cells of mesenchymal origin, the Mesenchymal Stem Cells (MSC). Frequent recurrence of LMS and chemoresistance of relapsed patients may likely result from the failure to target CSC. Therefore, therapeutic cues coming from the cancer stem cell (CSC) field may drastically improve patient outcome. Methodology/Principal Findings: We expanded LMS stem-like cells from patient samples in vitro and examined the possibility to counteract LMS malignancy through a stem-like cell effective approach. LMS stem-like cells were in vitro expanded both as "tumor spheres" and as "monolayers" in Mesenchymal Stem Cell (MSC) conditions. LMS stem-like cells displayed MSC phenotype, higher SP fraction, and increased drug-extrusion, extended proliferation potential, self-renewal, and multiple differentiation ability. They were chemoresistant, highly tumorigenic, and faithfully reproduced the patient tumor in mice. Such cells displayed activation of EGFR/AKT/MAPK pathways, suggesting a possibility in overcoming their chemoresistance through EGFR blockade. IRESSA plus Vincristine treatment determined pathway inactivation, impairment of SP phenotype, high cytotoxicity in vitro and strong antitumor activity in stem-like cell-generated patient-like xenografts, targeting both stem-like and differentiated cells. Conclusions/Significance: EGFR blockade combined with vincristine determines stem-like cell effective antitumor act
- Published
- 2012
44. Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma
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Tafani, Marco, Di Vito, Maura, Frati, Alessandro, Pellegrini, Laura, De Santis, Elena, Sette, Giovanni, Eramo, Adriana, Sale, Patrizio, Mari, Emanuela, Santoro, Antonio, Raco, Antonino, Salvati, Maurizio, De Maria Marchiano, Ruggero, Russo, Matteo A., De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Tafani, Marco, Di Vito, Maura, Frati, Alessandro, Pellegrini, Laura, De Santis, Elena, Sette, Giovanni, Eramo, Adriana, Sale, Patrizio, Mari, Emanuela, Santoro, Antonio, Raco, Antonino, Salvati, Maurizio, De Maria Marchiano, Ruggero, Russo, Matteo A., and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Background: Adaptation to hypoxia and consequent pro-inflammatory gene expression of prostate and breast carcinomas have been implicated in the progression toward cancer malignant phenotype. Only partial data are available for the human tumor glioblastoma multiforme (GBM). The aim of our study was to analyze the hypoxic and pro-inflammatory microenvironment in GBMs and to demonstrate that in a stem/progenitor cell line derived from human glioblastoma (GBM-SCs), hypoxia activates a coordinated inflammatory response, evidencing an invasive and migratory phenotype.Methods: From each of 10 human solid glioblastomas, clinically and histopathologically characterized, we obtained three surgical samples taken from the center and the periphery of the tumor, and from adjacent host normal tissue. Molecular and morphological analyses were carried out using quantitative real-time PCR and western blot (WB). GBM stem and differentiated cells were incubated under hypoxic conditions and analyzed for pro-inflammatory gene expression and for invasive/migratory behavior.Results: A panel of selected representative pro-inflammatory genes (RAGE and P2X7R, COX2, NOS2 and, PTX3) were analyzed, comparing tumor, peritumor and host normal tissues. Tumors containing leukocyte infiltrates (as assessed using CD45 immunohistochemistry) were excluded. Selected genes were overexpressed in the central regions of the tumors (i.e. in the more hypoxic areas), less expressed in peripheral regions, and poorly expressed or absent in adjacent normal host tissues. Western blot analysis confirmed that the corresponding pro-inflammatory proteins were also differently expressed. Hypoxic stem cell lines showed a clear time-dependent activation of the entire panel of pro-inflammatory genes as compared to differentiated tumor cells. Biological assays showed that invasive and migratory behavior was strengthened by hypoxia only in GBM stem cells.Conclusions: In human solid glioblastoma we have observed a coordinated
- Published
- 2011
45. Identification and expansion of the tumorigenic lung cancer stem cell population
- Author
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Eramo, A., Lotti, F., Sette, Giovanni, Pilozzi, E., Biffoni, M., Di Virgilio, A., Conticello, C., Ruco, L., Peschle, C., De Maria Marchiano, Ruggero, Sette, G., De Maria, R. (ORCID:0000-0003-2255-0583), Eramo, A., Lotti, F., Sette, Giovanni, Pilozzi, E., Biffoni, M., Di Virgilio, A., Conticello, C., Ruco, L., Peschle, C., De Maria Marchiano, Ruggero, Sette, G., and De Maria, R. (ORCID:0000-0003-2255-0583)
- Abstract
Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133+cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 104lung cancer CD133+cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133+cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133+cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.
- Published
- 2008
46. EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential
- Author
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Sette, Giovanni, primary, Salvati, Valentina, additional, Memeo, Lorenzo, additional, Fecchi, Katia, additional, Colarossi, Cristina, additional, Di Matteo, Paola, additional, Signore, Michele, additional, Biffoni, Mauro, additional, D’Andrea, Vito, additional, De Antoni, Enrico, additional, Canzonieri, Vincenzo, additional, De Maria, Ruggero, additional, and Eramo, Adriana, additional
- Published
- 2012
- Full Text
- View/download PDF
47. Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction
- Author
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Eramo, Adriana, Pallini, Roberto, Lotti, Fiorenza, Sette, Giovanni, Patti, Mariella, Bartucci, Monica, Ricci-Vitiani, Lucia, Signore, Michele, Stassi, Giorgio, Larocca, Luigi Maria, Crinò, Lucio, Peschle, Cesare, De Maria Marchiano, Ruggero, Pallini, Roberto (ORCID:0000-0002-4611-8827), Larocca, Luigi M. (ORCID:0000-0003-1739-4758), De Maria, Ruggero (ORCID:0000-0003-2255-0583), Eramo, Adriana, Pallini, Roberto, Lotti, Fiorenza, Sette, Giovanni, Patti, Mariella, Bartucci, Monica, Ricci-Vitiani, Lucia, Signore, Michele, Stassi, Giorgio, Larocca, Luigi Maria, Crinò, Lucio, Peschle, Cesare, De Maria Marchiano, Ruggero, Pallini, Roberto (ORCID:0000-0002-4611-8827), Larocca, Luigi M. (ORCID:0000-0003-1739-4758), and De Maria, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenous caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma resistance to therapeutic treatments. ©2005 American Association for Cancer Research.
- Published
- 2005
48. Use of PTEN status to determine the functional outcome of combined MEK and mTOR inhibition.
- Author
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Ciuffreda, Ludovica, primary, Falcone, Italia, additional, Cesta Incani, Ursula, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, Del Curatolo, Anais, additional, De Maria, Ruggero, additional, Cognetti, Francesco, additional, and Milella, Michele, additional
- Published
- 2012
- Full Text
- View/download PDF
49. CD95 death-inducing signaling complex formation and internalization occur in lipid rafts of type I and type II cells
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Eramo, Adriana, Sargiacomo, Massimo, Ricci-Vitiani, Lucia, Todaro, Matilde, Stassi, Giorgio, Messina, Carlo G. M., Parolini, Isabella, Lotti, Fiorenza, Sette, Giovanni, Peschle, Cesare, De Maria Marchiano, Ruggero, De Maria, Ruggero (ORCID:0000-0003-2255-0583), Eramo, Adriana, Sargiacomo, Massimo, Ricci-Vitiani, Lucia, Todaro, Matilde, Stassi, Giorgio, Messina, Carlo G. M., Parolini, Isabella, Lotti, Fiorenza, Sette, Giovanni, Peschle, Cesare, De Maria Marchiano, Ruggero, and De Maria, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
We investigated the membrane localization of CD95 in type I and type II cells, which differ in their ability to recruit and activate caspase-8. We found that CD95 was preferentially located in lipid rafts of type I cells, while it was present both in raft and non-raft plasma membrane sub-domains of type II cells. After stimulation, CD95 located in phospholipid-rich plasma membrane was recruited to lipid rafts in both types of cells. Similarly, CD95 cross-linking resulted in caspase-independent translocation of FADD/MORT1 and caspase-8 to the lipid rafts, which was prevented by a death domain-defective receptor. CD95 internalization was then rapid in type I and delayed in type II cells and showed a substantial correlation with the kinetics of Fas-associated death domain (FADD) and caspase-8 recruitment to lipid rafts. Finally, electron microscopy analysis showed that after CD95 stimulation lipid rafts aggregated in large clusters that were internalized in endosomal vesicles, where caspase-8 underwent massive processing. Taken together, our data demonstrate that CD95 death-inducing signaling complex formation and internalization in type I and type II cells occur in lipid rafts, which are a major site of caspase-8 activation. © 2004 WILEY-VCH Verlag GmbH & Co. KGaA.
- Published
- 2004
50. Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma
- Author
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Tafani, Marco, primary, Di Vito, Maura, additional, Frati, Alessandro, additional, Pellegrini, Laura, additional, De Santis, Elena, additional, Sette, Giovanni, additional, Eramo, Adriana, additional, Sale, Patrizio, additional, Mari, Emanuela, additional, Santoro, Antonio, additional, Raco, Antonino, additional, Salvati, Maurizio, additional, De Maria, Ruggero, additional, and Russo, Matteo A, additional
- Published
- 2011
- Full Text
- View/download PDF
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