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1. The new world of RNA diagnostics and therapeutics

Author

Blandino, Giovanni, Dinami, Roberto, Marcia, Marco, Anastasiadou, Eleni, Ryan, Brid M., Palcau, Alina Catalina, Fattore, Luigi, Regazzo, Giulia, Sestito, Rosanna, Loria, Rossella, Díaz Méndez, Ana Belén, Cappelletto, Maria Chiara, Pulito, Claudio, Monteonofrio, Laura, Calin, George A., Sozzi, Gabriella, Cheong, Jit Kong, Aharonov, Ranit, and Ciliberto, Gennaro

Published
2023
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2. SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

Author

Loria, Rossella, Laquintana, Valentina, Scalera, Stefano, Fraioli, Rocco, Caprara, Valentina, Falcone, Italia, Bazzichetto, Chiara, Di Martile, Marta, Rosanò, Laura, Del Bufalo, Donatella, Bossi, Gianluca, Sperduti, Isabella, Terrenato, Irene, Visca, Paolo, Soddu, Silvia, Milella, Michele, Ciliberto, Gennaro, Falcioni, Rita, Ferraresi, Virginia, and Bon, Giulia

Published
2022
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5. Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Author

Bon, Giulia, Pizzuti, Laura, Laquintana, Valentina, Loria, Rossella, Porru, Manuela, Marchiò, Caterina, Krasniqi, Eriseld, Barba, Maddalena, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Barchiesi, Giacomo, Mazzotta, Marco, Marinelli, Daniele, Tomao, Silverio, Marchetti, Paolo, Valerio, Maria Rosaria, Mirabelli, Rosanna, Russo, Antonio, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Giotta, Francesco, Garufi, Carlo, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Sanguineti, Giuseppe, Sperduti, Isabella, Sapino, Anna, De Maria, Ruggero, Leonetti, Carlo, Di Leo, Angelo, Ciliberto, Gennaro, Falcioni, Rita, and Vici, Patrizia

Published
2020
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10. Additional file 1 of SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

Author

Loria, Rossella, Laquintana, Valentina, Scalera, Stefano, Fraioli, Rocco, Caprara, Valentina, Falcone, Italia, Bazzichetto, Chiara, Di Martile, Marta, Rosanò, Laura, Del Bufalo, Donatella, Bossi, Gianluca, Sperduti, Isabella, Terrenato, Irene, Visca, Paolo, Soddu, Silvia, Milella, Michele, Ciliberto, Gennaro, Falcioni, Rita, Ferraresi, Virginia, and Bon, Giulia

Abstract

Additional file 1: Supplementary Fig. S1. A: shCtr and SEMA6A-depleted A3 cells plated on poly-l lysine coated slides were treated or not with RhoA activator and stained with anti-YAP (red signal) or B: with Phalloidin (red signal). GFP reporter gene expression revealed successful silencing induction. The cells were counterstained with Hoechst to highlight nuclei. Scale bar 10 μm. Supplementary Fig. S2. Fold change number of viable shCtrl and SEMA6A-depleted A3 and H2 cells untreated and treated for 48 h with 0,1 μM dabrafenib (A) and 0,1 μM dabrafenib+ 5 nM trametinib (B) as compared with untreated shCtrl 2/59 cells. The results are presented as mean +/− standard deviation of three independent experiments.

Published
2022
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11. SEMA6A/RhoA/YAP Axis Mediates Tumor-Stroma Interactions and Prevents Response to Dual BRAF/MEK Inhibition in BRAF-Mutant Melanoma

Author

Loria, Rossella, primary, Laquintana, Valentina, additional, Scalera, Stefano, additional, Fraioli, Rocco, additional, Caprara, Valentina, additional, Falcone, Italia, additional, Bazzichetto, Chiara, additional, Martile, Marta Di, additional, Rosanò, Laura, additional, Bufalo, Donatella Del, additional, Bossi, Gianluca, additional, Sperduti, Isabella, additional, Terrenato, Irene, additional, Visca, Paolo, additional, Soddu, Silvia, additional, Milella, Michele, additional, Ciliberto, Gennaro, additional, Falcioni, Rita, additional, Ferraresi, Virginia, additional, and Bon, Giulia, additional

Published
2021
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12. Additional file 1 of Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Author

Bon, Giulia, Pizzuti, Laura, Laquintana, Valentina, Loria, Rossella, Porru, Manuela, Marchiò, Caterina, Krasniqi, Eriseld, Barba, Maddalena, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, Verde, Nicla La, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Barchiesi, Giacomo, Mazzotta, Marco, Marinelli, Daniele, Tomao, Silverio, Marchetti, Paolo, Valerio, Maria Rosaria, Mirabelli, Rosanna, Russo, Antonio, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Giotta, Francesco, Garufi, Carlo, Cazzaniga, Marina, Medico, Pietro Del, Roselli, Mario, Sanguineti, Giuseppe, Sperduti, Isabella, Sapino, Anna, Maria, Ruggero De, Leonetti, Carlo, Leo, Angelo Di, Ciliberto, Gennaro, Falcioni, Rita, and Vici, Patrizia

Subjects
Data_FILES
Abstract

Additional file 1.

Published
2020
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13. Additional file 2 of Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Author

Bon, Giulia, Pizzuti, Laura, Laquintana, Valentina, Loria, Rossella, Porru, Manuela, Marchiò, Caterina, Krasniqi, Eriseld, Barba, Maddalena, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, Verde, Nicla La, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Barchiesi, Giacomo, Mazzotta, Marco, Marinelli, Daniele, Tomao, Silverio, Marchetti, Paolo, Valerio, Maria Rosaria, Mirabelli, Rosanna, Russo, Antonio, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Giotta, Francesco, Garufi, Carlo, Cazzaniga, Marina, Medico, Pietro Del, Roselli, Mario, Sanguineti, Giuseppe, Sperduti, Isabella, Sapino, Anna, Maria, Ruggero De, Leonetti, Carlo, Leo, Angelo Di, Ciliberto, Gennaro, Falcioni, Rita, and Vici, Patrizia

Subjects
Data_FILES
Abstract

Additional file 2.

Published
2020
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14. Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut melanoma

Author

Loria, Rossella, Falcone, Italia, Di Martile, Marta, Caprara, Valentina, Fraioli, Rocco, Laquintana, Valentina, Bon, Giulia, Rosano, Laura, Del Bufalo, Donatella, Ciuffreda, Ludovica, Ferraresi, Virginia, Milella, Michele, and Falcioni, Rita

Subjects
enzymes and coenzymes (carbohydrates), endocrine system diseases, melanoma, Rho-GTPase, skin and connective tissue diseases, neoplasms, digestive system diseases, Braf
Abstract

Background: Despite the promise of dual BRAF/MEK inhibition as a therapy for BRAF-mutant (BRAF-mut) melanoma, heterogeneous responses have been observed in patients, thus predictors of benefit from therapy are needed. We have previously identified semaphorin 6A (SEMA6A) as a BRAF-mut-associated protein involved in actin cytoskeleton remodeling. The purpose of the present study is to dissect the role of SEMA6A in the biology of BRAF-mut melanoma, and to explore its predictive potential towards dual BRAF/MEK inhibition. Methods: SEMA6A expression was assessed by immunohistochemistry in melanoma cohort RECI1 (N = 112) and its prognostic potential was investigated in BRAF-mut melanoma patients from DFCI and TCGA datasets (N = 258). The molecular mechanisms regulated by SEMA6A to sustain tumor aggressiveness and targeted therapy resistance were investigated in vitro by using BRAF-mut and BRAF-wt melanoma cell lines, an inducible SEMA6A silencing cell model and a microenvironment-mimicking fibroblasts-coculturing model. Finally, SEMA6A prediction of benefit from dual BRAF/MEK inhibition was investigated in melanoma cohort RECI2 (N = 14). Results: Our results indicate higher protein expression of SEMA6A in BRAF-mut compared with BRAF-wt melanoma patients and show that SEMA6A is a prognostic indicator in BRAF-mut melanoma from TCGA and DFCI patients cohorts. In BRAF-mut melanoma cells, SEMA6A coordinates actin cytoskeleton remodeling by the RhoA-dependent activation of YAP and dual BRAF/MEK inhibition by dabrafenib+trametinib induces SEMA6A/RhoA/YAP axis. In microenvironment-mimicking co-culture condition, fibroblasts confer to melanoma cells a proliferative stimulus and protect them from targeted therapies, whereas SEMA6A depletion rescues the efficacy of dual BRAF/MEK inhibition. Finally, in BRAF-mut melanoma patients treated with dabrafenib+trametinib, high SEMA6A predicts shorter recurrence-free interval. Conclusions: Overall, our results indicate that SEMA6A contributes to microenvironment-coordinated evasion of melanoma cells from dual BRAF/MEK inhibition and it might be a good candidate predictor of short-term benefit from dual BRAF/MEK inhibition.

Published
2020

15. Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade. The SePHER Study.

Author

Bon, Giulia, primary, Pizzuti, Laura, additional, Laquintana, Valentina, additional, Loria, Rossella, additional, Porru, Manuela, additional, Marchiò, Caterina, additional, Krasniqi, Erisled, additional, Barba, Maddalena, additional, Maugeri-Saccà, Marcello, additional, Gamucci, Teresa, additional, Berardi, Rossana, additional, Livi, Lorenzo, additional, Ficorella, Corrado, additional, Natoli, Clara, additional, Cortesi, Enrico, additional, Generali, Daniele, additional, Verde, Nicla La, additional, Cassano, Alessandra, additional, Bria, Emilio, additional, Moscetti, Luca, additional, Michelotti, Andrea, additional, Adamo, Vincenzo, additional, Zamagni, Claudio, additional, Tonini, Giuseppe, additional, Barchiesi, Giacomo, additional, Mazzotta, Marco, additional, Marinelli, Daniele, additional, Tomao, Silverio, additional, Marchetti, Paolo, additional, Valerio, Maria Rosaria, additional, Mirabelli, Rosanna, additional, Russo, Antonio, additional, Fabbri, Maria Agnese, additional, D'Ostilio, Nicola, additional, Veltri, Enzo, additional, Corsi, Domenico, additional, Garrone, Ornella, additional, Paris, Ida, additional, Sarobba, Giuseppina, additional, Giotta, Francesco, additional, Garufi, Carlo, additional, Cazzaniga, Marina, additional, Medico, Pietro Del, additional, Roselli, Mario, additional, Sanguineti, Giuseppe, additional, Sperduti, Isabella, additional, Sapino, Anna, additional, De Maria, Ruggero, additional, Leonetti, Carlo, additional, Leo, Angelo Di, additional, Ciliberto, Gennaro, additional, Falcioni, Rita, additional, and Vici, Patrizia, additional

Published
2020
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16. HER2 Nuclear Translocation and Decreased T-DM1 Efficacy in HER2 Positive Advanced Breast Cancer Treated with Dual HER2 Blockade. The SePHER Study.

Author

Bon, Giulia, primary, Pizzuti, Laura, additional, Laquintana, Valentina, additional, Loria, Rossella, additional, Porru, Manuela, additional, Marchiò, Caterina, additional, Krasniqi, Erisled, additional, Barba, Maddalena, additional, Maugeri-Saccà, Marcello, additional, Gamucci, Teresa, additional, Berardi, Rossana, additional, Livi, Lorenzo, additional, Ficorella, Corrado, additional, Natoli, Clara, additional, Cortesi, Enrico, additional, Generali, Daniele, additional, Verde, Nicla La, additional, Cassano, Alessandra, additional, Bria, Emilio, additional, Moscetti, Luca, additional, Michelotti, Andrea, additional, Adamo, Vincenzo, additional, Zamagni, Claudio, additional, Tonini, Giuseppe, additional, Barchiesi, Giacomo, additional, Mazzotta, Marco, additional, Marinelli, Daniele, additional, Tomao, Silverio, additional, Marchetti, Paolo, additional, Valerio, Maria Rosaria, additional, Mirabelli, Rosanna, additional, Russo, Antonio, additional, Fabbri, Maria Agnese, additional, D'Ostilio, Nicola, additional, Veltri, Enzo, additional, Corsi, Domenico, additional, Garrone, Ornella, additional, Paris, Ida, additional, Sarobba, Giuseppina, additional, Giotta, Francesco, additional, Garufi, Carlo, additional, Cazzaniga, Marina, additional, Medico, Pietro Del, additional, Roselli, Mario, additional, Sanguineti, Giuseppe, additional, Sperduti, Isabella, additional, Sapino, Anna, additional, De Maria, Ruggero, additional, Leonetti, Carlo, additional, Leo, Angelo Di, additional, Ciliberto, Gennaro, additional, Falcioni, Rita, additional, and Vici, Patrizia, additional

Published
2020
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17. Abstract 1887: Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut melanoma

Author

Loria, Rossella, primary, Falcone, Italia, additional, Martile, Marta Di, additional, Caprara, Valentina, additional, Fraioli, Rocco, additional, Laquintana, Valentina, additional, Bon, Giulia, additional, Rosanò, Laura, additional, Bufalo, Donatella Del, additional, Ciuffreda, Ludovica, additional, Ferraresi, Virginia, additional, Milella, Michele, additional, and Falcioni, Rita, additional

Published
2020
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18. Corrigendum: Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group

Author

Racanelli, Dominga, primary, Brenca, Monica, additional, Baldazzi, Davide, additional, Goeman, Frauke, additional, Casini, Beatrice, additional, De Angelis, Biagio, additional, Guercio, Marika, additional, Milano, Giuseppe Maria, additional, Tamborini, Elena, additional, Busico, Adele, additional, Dagrada, Gianpaolo, additional, Garofalo, Cecilia, additional, Caruso, Chiara, additional, Brunello, Antonella, additional, Pignochino, Ymera, additional, Berrino, Enrico, additional, Grignani, Giovanni, additional, Scotlandi, Katia, additional, Parra, Alessandro, additional, Hattinger, Claudia Maria, additional, Ibrahim, Toni, additional, Mercatali, Laura, additional, De Vita, Alessandro, additional, Carriero, Maria Vincenza, additional, Pallocca, Matteo, additional, Loria, Rossella, additional, Covello, Renato, additional, Sbaraglia, Marta, additional, Dei Tos, Angelo Paolo, additional, Falcioni, Rita, additional, and Maestro, Roberta, additional

Published
2020
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19. Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group

Author

Racanelli, Dominga, primary, Brenca, Monica, additional, Baldazzi, Davide, additional, Goeman, Frauke, additional, Casini, Beatrice, additional, De Angelis, Biagio, additional, Guercio, Marika, additional, Milano, Giuseppe Maria, additional, Tamborini, Elena, additional, Busico, Adele, additional, Dagrada, Gianpaolo, additional, Garofalo, Cecilia, additional, Caruso, Chiara, additional, Brunello, Antonella, additional, Pignochino, Ymera, additional, Berrino, Enrico, additional, Grignani, Giovanni, additional, Scotlandi, Katia, additional, Parra, Alessandro, additional, Hattinger, Claudia Maria, additional, Ibrahim, Toni, additional, Mercatali, Laura, additional, De Vita, Alessandro, additional, Carriero, Maria Vincenza, additional, Pallocca, Matteo, additional, Loria, Rossella, additional, Covello, Renato, additional, Sbaraglia, Marta, additional, Dei Tos, Angelo Paolo, additional, Falcioni, Rita, additional, and Maestro, Roberta, additional

Published
2020
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20. H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer

Author

Bacci, Lorenza, primary, Aiello, Aurora, additional, Ripoli, Cristian, additional, Loria, Rossella, additional, Pugliese, Dario, additional, Pierconti, Francesco, additional, Rotili, Dante, additional, Strigari, Lidia, additional, Pinto, Francesco, additional, Bassi, Pier Francesco, additional, Mai, Antonello, additional, Grassi, Claudio, additional, Pontecorvi, Alfredo, additional, Falcioni, Rita, additional, Farsetti, Antonella, additional, and Nanni, Simona, additional

Published
2019
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21. Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers

Author

Bon, Giulia, Loria, Rossella, Amoreo, Carla Azzurra, Verdina, Alessandra, Sperduti, Isabella, Mastrofrancesco, Arianna, Soddu, Silvia, Diodoro, Maria Grazia, Mottolese, Marcella, Todaro, Matilde, Stassi, Giorgio, Milella, Michele, De Maria Marchiano, Ruggero, Falcioni, Rita, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Bon, Giulia, Loria, Rossella, Amoreo, Carla Azzurra, Verdina, Alessandra, Sperduti, Isabella, Mastrofrancesco, Arianna, Soddu, Silvia, Diodoro, Maria Grazia, Mottolese, Marcella, Todaro, Matilde, Stassi, Giorgio, Milella, Michele, De Maria Marchiano, Ruggero, Falcioni, Rita, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)

Abstract

Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho- HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival. Targeting HER3 by the use of the monoclonal antibody patritumab we found induction of growth arrest in all cell lines. Despite the high efficiency of patritumab in abrogating the HER3-dependent activation of PI3K pathway, the HER2 and EGFRdependent MAPK pathway is activated as a compensatory mechanism. Interestingly, we found that the MEK-inhibitor trametinib inhibits, as expected, the MAPK pathway but induces the HER3-dependent activation of PI3K pathway. The combined treatment results in the abrogation of both PI3K and MAPK pathways and in a significant reduction of cell proliferation and survival. These data suggest a new strategy of therapy for HER3-overexpressing colon cancers.

Published
2017

23. Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers

Author

Bon, Giulia, primary, Loria, Rossella, additional, Amoreo, Carla Azzurra, additional, Verdina, Alessandra, additional, Sperduti, Isabella, additional, Mastrofrancesco, Arianna, additional, Soddu, Silvia, additional, Diodoro, Maria Grazia, additional, Mottolese, Marcella, additional, Todaro, Matilde, additional, Stassi, Giorgio, additional, Milella, Michele, additional, De Maria, Ruggero, additional, and Falcioni, Rita, additional

Published
2016
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24. Abstract 4721: Enhancement of doxorubicin cytotoxicity by histone deacetylase inhibition in human sarcoma cells

Author

Tupone, Maria Grazia, primary, Trisciuoglio, Daniela, additional, Desideri, Marianna, additional, Di Martile, Marta, additional, Buglioni, Simonetta, additional, Antoniani, Barbara, additional, Loria, Rossella, additional, Falcioni, Rita, additional, Milella, Michele, additional, Ferraresi, Virginia, additional, Di Pompo, Gemma, additional, Baldini, Nicola, additional, Biagini, Roberto, additional, and Del Bufalo, Donatella, additional

Published
2016
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26. Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells

Author

Loria, Rossella, primary, Bon, Giulia, additional, Perotti, Valentina, additional, Gallo, Enzo, additional, Bersani, Ilaria, additional, Baldassari, Paola, additional, Porru, Manuela, additional, Leonetti, Carlo, additional, Di Carlo, Selene, additional, Visca, Paolo, additional, Brizzi, Maria Felice, additional, Anichini, Andrea, additional, Mortarini, Roberta, additional, and Falcioni, Rita, additional

Published
2014
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27. Epitelial-to-mesenchimal transition and invasion are upmodulated by tumorexpressed granzyme B and inhibited by docosahexaenoic acid in human colorectal cancer cells.

Author

D'Eliseo, Donatella, Di Rocco, Giuliana, Loria, Rossella, Soddu, Silvia, Santoni, Angela, and Velotti, Francesca

Subjects
GRANZYMES, EPITHELIAL cells, COLON cancer, CANCER stem cells, UNSATURATED fatty acids, CANCER treatment
Abstract

Background: Granzyme B (GrB) is a serine protease, traditionally known as expressed by cytotoxic lymphocytes to induce target cell apoptosis. However, it is emerging that GrB, being also produced by a variety of normal and neoplastic cells and potentially acting on multiple targets, might represent a powerful regulator of a wide range of fundamental biological processes. We have previously shown that GrB is expressed in urothelial carcinoma tissues and its expression is associated to both pathological tumor spreading and EMT. We have also shown that docosahexaenoic acid (DHA), a dietary ?-3 polyunsaturated fatty acid with anti-tumor activity, while inhibiting urothelial and pancreatic carcinoma cell invasion also inhibited their GrB expression in vitro. In this study, we characterized a panel of colorectal carcinoma (CRC) cells, with different invasive capabilities, for GrB expression and for the contribution of GrB to their EMT and invasive phenotype. In addition, we investigated the effect of DHA on CRC cell-associated GrB expression, EMT and invasion. Methods: The expression levels of GrB and EMT-related markers were evaluated by Western blotting. GrB knockdown was performed by Stealth RNAi small interfering RNA silencing and ectopic GrB expression by transfection of human GrB vector. Cell invasion was determined by the BioCoat Matrigel invasion chamber test. Results: GrB was produced in 57.1 % CRC cell lines and 100 % CRC-derived Cancer Stem Cells. Although GrB was constitutive expressed in both invasive and noninvasive CRC cells, GrB depletion in invasive CRC cells downmodulated their invasion in vitro, suggesting a contribution of GrB to CRC invasiveness. GrB loss or gain of function downmodulated or upmodulated EMT, respectively, according to the analysis of cancer cell expression of three EMT biomarkers (Snail1, E-cadherin, N-cadherin). Moreover, TGF-β1-driven EMT was associated to the enhancement of GrB expression in CRC cell lines, and GrB depletion led to downmodulation of TGF-β1-driven EMT. In addition, DHA inhibited GrB expression, EMT and invasion in CRC cells in vitro. Conclusions: These findings present a novel role for GrB as upmodulator of EMT in CRC cells. Moreover, these results support the use of DHA, a dietary compound without toxic effects, as adjuvant in CRC therapy. [ABSTRACT FROM AUTHOR]

Published
2016
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28. Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Author

Nicla La Verde, Domenico Corsi, Patrizia Vici, Angelo Di Leo, Enzo Veltri, Lorenzo Livi, Marina Elena Cazzaniga, Laura Pizzuti, Pietro Del Medico, Caterina Marchiò, Maria Rosaria Valerio, Ornella Garrone, Giuseppina Sarobba, Rossella Loria, Gennaro Ciliberto, Eriseld Krasniqi, Marcello Maugeri-Saccà, Anna Sapino, Paolo Marchetti, Rossana Berardi, Rita Falcioni, Silverio Tomao, Clara Natoli, Vincenzo Adamo, Valentina Laquintana, Maddalena Barba, Claudio Zamagni, Maria Agnese Fabbri, Carlo Garufi, Giulia Bon, Giuseppe Sanguineti, Giacomo Barchiesi, Enrico Cortesi, Rosanna Mirabelli, Francesco Giotta, Nicola D’Ostilio, Giuseppe Tonini, Emilio Bria, Daniele Marinelli, Manuela Porru, Luca Moscetti, Marco Mazzotta, Ida Paris, Andrea Michelotti, Mario Roselli, Alessandra Cassano, Teresa Gamucci, Antonio Russo, Isabella Sperduti, Corrado Ficorella, Daniele Generali, Ruggero De Maria, Carlo Leonetti, Bon G., Pizzuti L., Laquintana V., Loria R., Porru M., Marchio C., Krasniqi E., Barba M., Maugeri-Sacca M., Gamucci T., Berardi R., Livi L., Ficorella C., Natoli C., Cortesi E., Generali D., La Verde N., Cassano A., Bria E., Moscetti L., Michelotti A., Adamo V., Zamagni C., Tonini G., Barchiesi G., Mazzotta M., Marinelli D., Tomao S., Marchetti P., Valerio M.R., Mirabelli R., Russo A., Fabbri M.A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Giotta F., Garufi C., Cazzaniga M., Del Medico P., Roselli M., Sanguineti G., Sperduti I., Sapino A., De Maria R., Leonetti C., Di Leo A., Ciliberto G., Falcioni R., Vici P., Bon, Giulia, Pizzuti, Laura, Laquintana, Valentina, Loria, Rossella, Porru, Manuela, Marchiò, Caterina, Krasniqi, Eriseld, Barba, Maddalena, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Barchiesi, Giacomo, Mazzotta, Marco, Marinelli, Daniele, Tomao, Silverio, Marchetti, Paolo, Valerio, Maria Rosaria, Mirabelli, Rosanna, Russo, Antonio, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Giotta, Francesco, Garufi, Carlo, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Sanguineti, Giuseppe, Sperduti, Isabella, Sapino, Anna, De Maria, Ruggero, Leonetti, Carlo, Di Leo, Angelo, Ciliberto, Gennaro, Falcioni, Rita, Vici, Patrizia, Bon, G, Pizzuti, L, Laquintana, V, Loria, R, Porru, M, Marchio, C, Krasniqi, E, Barba, M, Maugeri-Sacca, M, Gamucci, T, Berardi, R, Livi, L, Ficorella, C, Natoli, C, Cortesi, E, Generali, D, La Verde, N, Cassano, A, Bria, E, Moscetti, L, Michelotti, A, Adamo, V, Zamagni, C, Tonini, G, Barchiesi, G, Mazzotta, M, Marinelli, D, Tomao, S, Marchetti, P, Valerio, M, Mirabelli, R, Russo, A, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Giotta, F, Garufi, C, Cazzaniga, M, Del Medico, P, Roselli, M, Sanguineti, G, Sperduti, I, Sapino, A, De Maria, R, Leonetti, C, Di Leo, A, Ciliberto, G, Falcioni, R, and Vici, P

Subjects
0301 basic medicine, Oncology, Cancer Research, Receptor, ErbB-2, Apoptosis, Ado-Trastuzumab Emtansine, Settore MED/06, chemistry.chemical_compound, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, skin and connective tissue diseases, Aged, 80 and over, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, 030220 oncology & carcinogenesis, Female, Pertuzumab, medicine.drug, T-DM1 efficacy, musculoskeletal diseases, Adult, medicine.medical_specialty, HER2+ breast cancer, Trastuzumab/pertuzumab blockade, Breast Neoplasms, Antibodies, Monoclonal, Humanized, lcsh:RC254-282, 03 medical and health sciences, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Biomarkers, Tumor, Humans, neoplasms, Aged, Cell Proliferation, Retrospective Studies, Taxane, business.industry, Research, Cancer, medicine.disease, Blockade, Log-rank test, 030104 developmental biology, chemistry, Trastuzumab emtansine, Cancer cell, business
Abstract

BackgroundHER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.MethodsThe biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.ResultsWe herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients.Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).ConclusionsOur data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

Published
2020

29. Prognostic role of NF-YA splicing isoforms and Lamin A status in low grade endometrial cancer.

Author

Cicchillitti L, Corrado G, Carosi M, Dabrowska ME, Loria R, Falcioni R, Cutillo G, Piaggio G, and Vizza E

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, CCAAT-Binding Factor genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Endometrial Neoplasms surgery, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, Hysterectomy, Lamin Type A genetics, Middle Aged, Neoplasm Grading, Protein Isoforms, RNA, Messenger genetics, Receptors, Estrogen analysis, Retrospective Studies, Biomarkers, Tumor analysis, CCAAT-Binding Factor analysis, Endometrial Neoplasms chemistry, Lamin Type A analysis
Abstract

Although most cases of low grade (G1) endometrial cancer (EC) do not behave aggressively, in rare instances, can progress in a highly aggressive manner. In this study we analyzed formalin-fixed, paraffin-embedded (FFPE) EC tissues to find novel clinical and biological features to help diagnosis and treatment of G1 ECs s in order to better stratify patient risk of recurrence. A retrospective cohort of FFPE specimens from patients with EC (n=87) and benign tissue specimens (NE) from patients who underwent a hysterectomy to treat other benign disease (n = 13) were collected. Total RNA and proteins were extracted and analyzed, respectively, by quantitative PCR and western blotting. NF-YAs is expressed and lamin A is down-modulated in all high grade (G2 and G3) ECs. In G1 ECs, NF-YAs expression is heterogeneous being expressed only in a subset of these tumours. Interestingly, the G1 ECs that express NF-YAs display low levels of lamin A similar to those present in G2 and G3 ECs. Of note, this pattern of NF-YAs and lamin A expression correlates with tumor aggressiveness assessed by comparative analysis with estrogen receptor (ER) status and epithelial-mesenchymal transition (EMT) markers thus suggesting its potential role as biomarker of tumour aggressiveness in G1 EC. In all grade ECs, lamin A is strongly downmodulated, being its expression inversely correlated with tumor aggressiveness and its loss of expression. We identified NF-YAs and lamin A expression levels as novel potential biomarkers useful to identify G1 ECs patients with risk of recurrence.

Published
2017
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30. Epitelial-to-mesenchimal transition and invasion are upmodulated by tumor-expressed granzyme B and inhibited by docosahexaenoic acid in human colorectal cancer cells.

Author

D'Eliseo D, Di Rocco G, Loria R, Soddu S, Santoni A, and Velotti F

Subjects
Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Gene Expression Regulation, Neoplastic drug effects, Gene Knockdown Techniques, Granzymes genetics, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Up-Regulation drug effects, Antineoplastic Agents pharmacology, Colorectal Neoplasms metabolism, Docosahexaenoic Acids pharmacology, Epithelial-Mesenchymal Transition drug effects, Granzymes metabolism
Abstract

Background: Granzyme B (GrB) is a serine protease, traditionally known as expressed by cytotoxic lymphocytes to induce target cell apoptosis. However, it is emerging that GrB, being also produced by a variety of normal and neoplastic cells and potentially acting on multiple targets, might represent a powerful regulator of a wide range of fundamental biological processes. We have previously shown that GrB is expressed in urothelial carcinoma tissues and its expression is associated to both pathological tumor spreading and EMT. We have also shown that docosahexaenoic acid (DHA), a dietary ω-3 polyunsaturated fatty acid with anti-tumor activity, while inhibiting urothelial and pancreatic carcinoma cell invasion also inhibited their GrB expression in vitro. In this study, we characterized a panel of colorectal carcinoma (CRC) cells, with different invasive capabilities, for GrB expression and for the contribution of GrB to their EMT and invasive phenotype. In addition, we investigated the effect of DHA on CRC cell-associated GrB expression, EMT and invasion., Methods: The expression levels of GrB and EMT-related markers were evaluated by Western blotting. GrB knockdown was performed by Stealth RNAi small interfering RNA silencing and ectopic GrB expression by transfection of human GrB vector. Cell invasion was determined by the BioCoat Matrigel invasion chamber test., Results: GrB was produced in 57.1% CRC cell lines and 100% CRC-derived Cancer Stem Cells. Although GrB was constitutive expressed in both invasive and noninvasive CRC cells, GrB depletion in invasive CRC cells downmodulated their invasion in vitro, suggesting a contribution of GrB to CRC invasiveness. GrB loss or gain of function downmodulated or upmodulated EMT, respectively, according to the analysis of cancer cell expression of three EMT biomarkers (Snail1, E-cadherin, N-cadherin). Moreover, TGF-β1-driven EMT was associated to the enhancement of GrB expression in CRC cell lines, and GrB depletion led to downmodulation of TGF-β1-driven EMT. In addition, DHA inhibited GrB expression, EMT and invasion in CRC cells in vitro., Conclusions: These findings present a novel role for GrB as upmodulator of EMT in CRC cells. Moreover, these results support the use of DHA, a dietary compound without toxic effects, as adjuvant in CRC therapy.

Published
2016
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31. Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells.

Author

Loria R, Bon G, Perotti V, Gallo E, Bersani I, Baldassari P, Porru M, Leonetti C, Di Carlo S, Visca P, Brizzi MF, Anichini A, Mortarini R, and Falcioni R

Subjects
Actin Cytoskeleton metabolism, Adaptor Proteins, Signal Transducing genetics, Animals, Apoptosis, Blotting, Western, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Survival, Cytoskeletal Proteins genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Humans, Immunohistochemistry, LIM Domain Proteins genetics, Male, Melanoma genetics, Melanoma pathology, Mice, Nude, Microfilament Proteins, Mixed Function Oxygenases, Neoplasm Invasiveness, Nuclear Proteins genetics, Nuclear Proteins metabolism, Oligonucleotide Array Sequence Analysis, Phosphorylation, RNA Interference, Real-Time Polymerase Chain Reaction, Semaphorins genetics, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms pathology, Transfection, Adaptor Proteins, Signal Transducing metabolism, Cell Proliferation, Cytoskeletal Proteins metabolism, LIM Domain Proteins metabolism, Melanoma enzymology, Mutation, Proto-Oncogene Proteins B-raf genetics, Semaphorins metabolism, Skin Neoplasms enzymology
Abstract

We used whole genome microarray analysis to identify potential candidate genes with differential expression in BRAFV600E vs NRASQ61R melanoma cells. We selected, for comparison, a peculiar model based on melanoma clones, isolated from a single tumor characterized by mutually exclusive expression of BRAFV600E and NRASQ61R in different cells. This effort led us to identify two genes, SEMA6A and MICAL1, highly expressed in BRAF-mutant vs NRAS-mutant clones. Real-time PCR, Western blot and immunohistochemistry confirmed preferential expression of Sema6A and Mical1 in BRAFV600E melanoma. Sema6A is a member of the semaphorin family, and it complexes with the plexins to regulate actin cytoskeleton, motility and cell proliferation. Silencing of Sema6A in BRAF-mutant cells caused cytoskeletal remodeling, and loss of stress fibers, that in turn induced cell death. Furthermore, Sema6A depletion caused loss of anchorage-independent growth, inhibition of chemotaxis and invasion. Forced Sema6A overexpression, in NRASQ61R clones, induced anchorage-independent growth, and a significant increase of invasiveness. Mical1, that links Sema/PlexinA signaling, is also a negative regulator of apoptosis. Indeed, Mical-1 depletion in BRAF mutant cells restored MST-1-dependent NDR phosphorylation and promoted a rapid and massive NDR-dependent apoptosis. Overall, our data suggest that Sema6A and Mical1 may represent new potential therapeutic targets in BRAFV600E melanoma.

Published
2015
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