218 results on '"Signore, Michele"'
Search Results
2. HDAC3 genetic and pharmacologic inhibition radiosensitizes fusion positive rhabdomyosarcoma by promoting DNA double-strand breaks
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Cassandri, Matteo, Porrazzo, Antonella, Pomella, Silvia, Noce, Beatrice, Zwergel, Clemens, Aiello, Francesca Antonella, Vulcano, Francesca, Milazzo, Luisa, Camero, Simona, Pajalunga, Deborah, Spada, Massimo, Manzi, Valeria, Gravina, Giovanni Luca, Codenotti, Silvia, Piccione, Michela, Tomaciello, Miriam, Signore, Michele, Barillari, Giovanni, Marchese, Cinzia, Fanzani, Alessandro, De Angelis, Biagio, Quintarelli, Concetta, Vakoc, Christopher R., Chen, Eleanor Y., Megiorni, Francesca, Locatelli, Franco, Valente, Sergio, Mai, Antonello, Rota, Rossella, and Marampon, Francesco
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- 2024
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3. Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2
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Abbruzzese, Claudia, Matteoni, Silvia, Matarrese, Paola, Signore, Michele, Ascione, Barbara, Iessi, Elisabetta, Gurtner, Aymone, Sacconi, Andrea, Ricci-Vitiani, Lucia, Pallini, Roberto, Pace, Andrea, Villani, Veronica, Polo, Andrea, Costantini, Susan, Budillon, Alfredo, Ciliberto, Gennaro, and Paggi, Marco G.
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- 2023
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4. Flow-dependent shear stress affects the biological properties of pericyte-like cells isolated from human dental pulp
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Bertani, Giulia, Di Tinco, Rosanna, Bertoni, Laura, Orlandi, Giulia, Pisciotta, Alessandra, Rosa, Roberto, Rigamonti, Luca, Signore, Michele, Bertacchini, Jessika, Sena, Paola, De Biasi, Sara, Villa, Erica, and Carnevale, Gianluca
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- 2023
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5. An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile
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De Angelis, Maria Laura, Francescangeli, Federica, Nicolazzo, Chiara, Signore, Michele, Giuliani, Alessandro, Colace, Lidia, Boe, Alessandra, Magri, Valentina, Baiocchi, Marta, Ciardi, Antonio, Scarola, Francesco, Spada, Massimo, La Torre, Filippo, Gazzaniga, Paola, Biffoni, Mauro, De Maria, Ruggero, and Zeuner, Ann
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- 2022
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6. Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51
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Manic, Gwenola, Musella, Martina, Corradi, Francesca, Sistigu, Antonella, Vitale, Sara, Soliman Abdel Rehim, Sara, Mattiello, Luca, Malacaria, Eva, Galassi, Claudia, Signore, Michele, Pallocca, Matteo, Scalera, Stefano, Goeman, Frauke, De Nicola, Francesca, Guarracino, Andrea, Pennisi, Rosa, Antonangeli, Fabrizio, Sperati, Francesca, Baiocchi, Marta, Biffoni, Mauro, Fanciulli, Maurizio, Maugeri-Saccà, Marcello, Franchitto, Annapaola, Pichierri, Pietro, De Maria, Ruggero, and Vitale, Ilio
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- 2021
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7. Chlorpromazine overcomes temozolomide resistance in glioblastoma by inhibiting Cx43 and essential DNA repair pathways.
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Matarrese, Paola, Signore, Michele, Ascione, Barbara, Fanelli, Giulia, Paggi, Marco G., and Abbruzzese, Claudia
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METHYLGUANINE , *DNA repair , *CHLORPROMAZINE , *TEMOZOLOMIDE , *GENE expression , *CELL death , *PROTEIN microarrays - Abstract
Background: In the fight against GBM, drug repurposing emerges as a viable and time-saving approach to explore new treatment options. Chlorpromazine, an old antipsychotic medication, has recently arisen as a promising candidate for repositioning in GBM therapy in addition to temozolomide, the first-line standard of care. We previously demonstrated the antitumor efficacy of chlorpromazine and its synergistic effects with temozolomide in suppressing GBM cell malignant features in vitro. This prompted us to accomplish a Phase II clinical trial to evaluate the efficacy and safety of adding chlorpromazine to temozolomide in GBM patients with unmethylated MGMT gene promoter. In this in vitro study, we investigate the potential role of chlorpromazine in overcoming temozolomide resistance. Methods: In our experimental set, we analyzed Connexin-43 expression at both the transcriptional and protein levels in control- and chlorpromazine-treated GBM cells. DNA damage and subsequent repair were assessed by immunofluorescence of γ-H2AX and Reverse-Phase Protein microArrays in chlorpromazine treated GBM cell lines. To elucidate the relationship between DNA repair systems and chemoresistance, we analyzed a signature of DNA repair genes in GBM cells after treatment with chlorpromazine, temozolomide and Connexin-43 downregulation. Results: Chlorpromazine treatment significantly downregulated connexin-43 expression in GBM cells, consequently compromising connexin-dependent cellular resilience, and ultimately contributing to cell death. In line with this, we observed concordant post-translational modifications of molecular determinants involved in DNA damage and repair pathways. Our evaluation of DNA repair genes revealed that temozolomide elicited an increase, while chlorpromazine, as well as connexin-43 silencing, a decrease in DNA repair gene expression in GBM cells. Conclusions: Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
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Buccarelli, Mariachiara, D’Alessandris, Quintino Giorgio, Matarrese, Paola, Mollinari, Cristiana, Signore, Michele, Cappannini, Andrea, Martini, Maurizio, D’Aliberti, Pierluigi, De Luca, Gabriele, Pedini, Francesca, Boe, Alessandra, Biffoni, Mauro, Pallini, Roberto, and Ricci-Vitiani, Lucia
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- 2021
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9. Stem-Like Adaptive Aneuploidy and Cancer Quasispecies
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Napoletani, Domenico, Signore, Michele, and Struppa, Daniele C.
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Quantitative Biology - Cell Behavior ,Quantitative Biology - Genomics - Abstract
We analyze and reinterpret experimental evidence from the literature to argue for an ability of tumor cells to self-regulate their aneuploidy rate. We conjecture that this ability is mediated by a diversification factor that exploits molecular mechanisms common to embryo stem cells and, to a lesser extent, adult stem cells, that is eventually reactivated in tumor cells. Moreover, we propose a direct use of the quasispecies model to cancer cells based on their significant genomic instability (i.e. aneuploidy rate), by defining master sequences lengths as the sum of all copy numbers of physically distinct whole and fragmented chromosomes. We compute an approximate error threshold such that any aneuploidy rate larger than the threshold would lead to a loss of fitness of a tumor population, and we confirm that highly aneuploid cancer populations already function with aneuploidy rates close to the estimated threshold.
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- 2013
10. Homologous Control of Protein Signaling Networks
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Napoletani, Domenico, Signore, Michele, Sauer, Timothy, Liotta, Lance, and Petricoin, Emanuel
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Quantitative Biology - Molecular Networks ,Physics - Biological Physics ,Physics - Data Analysis, Statistics and Probability ,Physics - Medical Physics - Abstract
In a previous paper we introduced a method called augmented sparse reconstruction (ASR) that identifies links among nodes of ordinary differential equation networks, given a small set of observed trajectories with various initial conditions. The main purpose of that technique was to reconstruct intracellular protein signaling networks. In this paper we show that a recursive augmented sparse reconstruction generates artificial networks that are homologous to a large, reference network, in the sense that kinase inhibition of several reactions in the network alters the trajectories of a sizable number of proteins in comparable ways for reference and reconstructed networks. We show this result using a large in-silico model of the epidermal growth factor receptor (EGF-R) driven signaling cascade to generate the data used in the reconstruction algorithm. The most significant consequence of this observed homology is that a nearly optimal combinatorial dosage of kinase inhibitors can be inferred, for many nodes, from the reconstructed network, a result potentially useful for a variety of applications in personalized medicine., Comment: 33 pages, 6 figures
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- 2010
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11. Diagnostic and prognostic potential of the proteomic profiling of serum-derived extracellular vesicles in prostate cancer
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Signore, Michele, Alfonsi, Romina, Federici, Giulia, Nanni, Simona, Addario, Antonio, Bertuccini, Lucia, Aiello, Aurora, Di Pace, Anna Laura, Sperduti, Isabella, Muto, Giovanni, Giacobbe, Alessandro, Collura, Devis, Brunetto, Lidia, Simone, Giuseppe, Costantini, Manuela, Crinò, Lucio, Rossi, Stefania, Tabolacci, Claudio, Diociaiuti, Marco, Merlino, Tania, Gallucci, Michele, Sentinelli, Steno, Papalia, Rocco, De Maria, Ruggero, and Bonci, Désirée
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- 2021
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12. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer
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Francescangeli, Federica, Contavalli, Paola, De Angelis, Maria Laura, Careccia, Silvia, Signore, Michele, Haas, Tobias Longin, Salaris, Federico, Baiocchi, Marta, Boe, Alessandra, Giuliani, Alessandro, Tcheremenskaia, Olga, Pagliuca, Alfredo, Guardiola, Ombretta, Minchiotti, Gabriella, Colace, Lidia, Ciardi, Antonio, D’Andrea, Vito, La Torre, Filippo, Medema, JanPaul, De Maria, Ruggero, and Zeuner, Ann
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- 2020
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13. 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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14. 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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15. Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases
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Grassi, Ludovica, Alfonsi, Romina, Francescangeli, Federica, Signore, Michele, De Angelis, Maria Laura, Addario, Antonio, Costantini, Manuela, Flex, Elisabetta, Ciolfi, Andrea, Pizzi, Simone, Bruselles, Alessandro, Pallocca, Matteo, Simone, Giuseppe, Haoui, Mustapha, Falchi, Mario, Milella, Michele, Sentinelli, Steno, Di Matteo, Paola, Stellacci, Emilia, Gallucci, Michele, Muto, Giovanni, Tartaglia, Marco, De Maria, Ruggero, and Bonci, Désirée
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- 2019
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16. Additional file 1 of Flow-dependent shear stress affects the biological properties of pericyte-like cells isolated from human dental pulp
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Bertani, Giulia, Di Tinco, Rosanna, Bertoni, Laura, Orlandi, Giulia, Pisciotta, Alessandra, Rosa, Roberto, Rigamonti, Luca, Signore, Michele, Bertacchini, Jessika, Sena, Paola, De Biasi, Sara, Villa, Erica, and Carnevale, Gianluca
- Abstract
Additional file 1: Figure S1. Extended data for figure 3 and 4. Uncropped Western blot images showing A PDGFR-β and related actin; B cleaved caspase-3 and related actin; C eNOS and VEGF with related actin; D Tie2, ANGPT1 and related actin. Boxed areas correspond to cropped regions shown in figure 3C and 3E. Specific target bands were selected according to the molecular weight reported in antibodies’ datasheets. Table S1: raw RPPA data.
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- 2023
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17. Renal cancer: new models and approach for personalizing therapy
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di Martino, Simona, De Luca, Gabriele, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, De Salvo, Laura, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Sentinelli, Steno, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, De Maria, Ruggero, and Bonci, Désirée
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- 2018
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18. Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B
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Musella, Martina, Guarracino, Andrea, Manduca, Nicoletta, Galassi, Claudia, Ruggiero, Eliana, Potenza, Alessia, Maccafeo, Ester, Manic, Gwenola, Mattiello, Luca, Soliman Abdel Rehim, Sara, Signore, Michele, Pietrosanto, Marco, Helmer-Citterich, Manuela, Pallocca, Matteo, Fanciulli, Maurizio, Bruno, Tiziana, De Nicola, Francesca, Corleone, Giacomo, Di Benedetto, Anna, Ercolani, Cristiana, Pescarmona, Edoardo, Pizzuti, Laura, Guidi, Francesco, Sperati, Francesca, Vitale, Sara, Macchia, Daniele, Spada, Massimo, Schiavoni, Giovanna, Mattei, Fabrizio, De Ninno, Adele, Businaro, Luca, Lucarini, Valeria, Bracci, Laura, Aricò, Eleonora, Ziccheddu, Giovanna, Facchiano, Francesco, Rossi, Stefania, Sanchez, Massimo, Boe, Alessandra, Biffoni, Mauro, De Maria Marchiano, Ruggero, Vitale, Ilio, Sistigu, Antonella, De Maria, Ruggero (ORCID:0000-0003-2255-0583), Sistigu, Antonella (ORCID:0000-0002-2528-1238), Musella, Martina, Guarracino, Andrea, Manduca, Nicoletta, Galassi, Claudia, Ruggiero, Eliana, Potenza, Alessia, Maccafeo, Ester, Manic, Gwenola, Mattiello, Luca, Soliman Abdel Rehim, Sara, Signore, Michele, Pietrosanto, Marco, Helmer-Citterich, Manuela, Pallocca, Matteo, Fanciulli, Maurizio, Bruno, Tiziana, De Nicola, Francesca, Corleone, Giacomo, Di Benedetto, Anna, Ercolani, Cristiana, Pescarmona, Edoardo, Pizzuti, Laura, Guidi, Francesco, Sperati, Francesca, Vitale, Sara, Macchia, Daniele, Spada, Massimo, Schiavoni, Giovanna, Mattei, Fabrizio, De Ninno, Adele, Businaro, Luca, Lucarini, Valeria, Bracci, Laura, Aricò, Eleonora, Ziccheddu, Giovanna, Facchiano, Francesco, Rossi, Stefania, Sanchez, Massimo, Boe, Alessandra, Biffoni, Mauro, De Maria Marchiano, Ruggero, Vitale, Ilio, Sistigu, Antonella, De Maria, Ruggero (ORCID:0000-0003-2255-0583), and Sistigu, Antonella (ORCID:0000-0002-2528-1238)
- Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I -> KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.
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- 2022
19. Additional file 1 of An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile
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De Angelis, Maria Laura, Francescangeli, Federica, Nicolazzo, Chiara, Signore, Michele, Giuliani, Alessandro, Colace, Lidia, Boe, Alessandra, Magri, Valentina, Baiocchi, Marta, Ciardi, Antonio, Scarola, Francesco, Spada, Massimo, La Torre, Filippo, Gazzaniga, Paola, Biffoni, Mauro, De Maria, Ruggero, and Zeuner, Ann
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Additional file 1:. Supplementary Methods.
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- 2022
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20. Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells
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Sacchetti Benedetto, Fatica Alessandro, Sorci Melissa, Sorrentino Antonio, Signore Michele, Cerio Annamaria, Felicetti Federica, Feo Alessandra De, Pelosi Elvira, Caré Alessandra, Pescarmona Edoardo, Gordeladze Jan Oxholm, and Valtieri Mauro
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Mesenchymal stromal cells ,miR-204 ,RUNX2 ,cartilage ,hematopoietic support activity ,osteogenesis ,adipogenesis ,Medicine - Abstract
MiR-204 and 211 enforced expression in murine mesenchymal stromal cells (MSCs) has been shown to induce adipogenesis and impair osteogenesis, through RUNX2 down-modulation. This mechanism has been suggested to play a role in osteoporosis associated with obesity. However, two further fundamental MSC functions, chondrogenesis and hematopoietic supporting activity, have not yet been explored. To this end, we transduced, by a lenti-viral vector, miR-204 and 211 in a model primary human MSC line, opportunely chosen among our MSC collection for displaying all properties of canonical bone marrow MSCs, except adipogenesis. Enforced expression of miR-204&211 in these cells, rescued adipogenesis, and inhibited osteogenesis, as previously reported in murine MSCs, but, surprisingly, also damaged cartilage formation and hematopoietic supporting activity, which were never explored before. RUNX2 has been previously indicated as the target of miR-204&211, whose down modulation is responsible for the switch from osteogenesis to adipogenesis. However, the additional disruption of chondrogenesis and hematopoietic supporting activity, which we report here, might depend on diverse miR-204&211 targets. To investigate this hypothesis, permanent RUNX2 knock-down was performed. Sh-RUNX2 fully reproduced the phenotypes induced by miR-204&211, confirming that RUNX2 down modulation is the major event leading to the reported functional modification on our MSCs. It seems thus apparent that RUNX2, a recognized master gene for osteogenesis, might rule all four MSC commitment and differentiation processes. Hence, the formerly reported role of miR204&211 and RUNX2 in osteoporosis and obesity, coupled with our novel observation showing inhibition of cartilage differentiation and hematopoietic support, strikingly resemble the clinical traits of metabolic syndrome, where osteoarthritis, osteoporosis, anaemia and obesity occur together. Our observations, corroborating and extending previous observations, suggest that miR-204&211–RUNX2 axis in human MSCs is possibly involved in the pathogenesis of this rapidly growing disease in industrialized countries, for possible therapeutic intervention to regenerate former homeostasis.
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- 2017
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21. Additional file 1 of Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
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Buccarelli, Mariachiara, D’Alessandris, Quintino Giorgio, Matarrese, Paola, Mollinari, Cristiana, Signore, Michele, Cappannini, Andrea, Martini, Maurizio, D’Aliberti, Pierluigi, De Luca, Gabriele, Pedini, Francesca, Boe, Alessandra, Biffoni, Mauro, Pallini, Roberto, and Ricci-Vitiani, Lucia
- Abstract
Additional file 1: Supplementary Table 1. List of drugs used for small-molecule kinase inhibitor screening (10 mM in DMSO). Supplementary Table 2. List of antibodies used for Reverse-Phase Protein microArrays (RPPA) analysis. Supplementary Table 3. Patient and GSC line characteristics. Supplementary Table 4. List of genes corresponding to significant antibodies and grouped using the Venn diagram in Fig. 4C. Supplementary Figure S1. A-D. Morphological changes of the four GSC lines used in the study (A, GSC#1; B, GSC#61; C, GSC#83; D, GSC#163) after being induced to transdifferentiate for 2 weeks. Left panel, tumorspheres in stem cell medium; right panel, net-like structures under endothelial conditions (magnification 10X). Supplementary Figure S2. (A) Fluorescent-activated cell sorting dot plots of CD34−/low and CD34high GSC#163 after two weeks of culture in endothelial conditions under hypoxia. Percentage and squares indicate the sorted subpopulations of cells with different CD34-expression levels (left, IgG1 isotype control sample; right, CD34 sample). (B-C) Immunohistochemical analysis of CD34low (B) and CD34high (C) GdEC subcutaneous tumor xenografts based on the expression of the astrocytic marker glial fibrillary acidic protein (GFAP, right panels), showing tumors with different levels of differentiation. (Left panels, haematoxylin and eosin staining; magnification 200X). Supplementary Figure S3. Concentration-response assays on U87MG and all the four glial cell lines derived from the selected GSC lines. Supplementary Figure S4. Cytofluorimetric cell-by-cell analysis of viability in four different GSC lines treated with 10, 100, or 1000 nM elesclomol in the presence or absence of the following cell death inhibitors: z-VAD, necrostatin-1, ferrostatin-1, 3-MA, NAC, and CoQ at the indicated concentrations. Results obtained from four independent experiments are expressed as percentage vs control untreated cells and reported as means ± SD. Supplementary Figure S5. Cytofluorimetric cell-by-cell analysis of cell viability (A), mitochondrial ROS production (B), mitochondrial membrane potential (C), and GSH (D) in four different GSC lines treated with 10, 100, or 1000 nM elesclomol in the presence or absence of the copper chelating agent TTM. Results obtained from four independent experiments are expressed as percentage vs control untreated cells and reported as means ± SD. Supplementary Figure S6. Cytofluorimetric cell-by-cell analysis of cell viability, mitochondrial ROS production, mitochondrial membrane potential, and GSH in HMVECs, used as a control of nontumoral endothelial cell line, treated with 10, 100, or 1000 nM Elesclomol in the presence or absence of the copper chelating agent TTM. Results obtained from four independent experiments are expressed as percentage vs control untreated cells and reported as means ± SD. Supplementary Figure S7. Illustration of the rationale suitable for the choice of rank k, a critical parameter that defines the number of metagenes used to approximate the target matrix (Gaujoux & Seoighe, 2010). A) Measurements are applied to both real data (circles) and randomized data (triangles). The rationale for choosing rank stems on diverse metrics, i) trend of the cophenetic coefficient: Brunet et al. (2004) suggest choosing the smallest value of k for which there is a decrease in the trend of the cophenetic; ii) trend of the dispersion coefficient introduced by Kim & Park. (2007); iii) explained variance by increasing rank; iv) trend of residuals; v) trend of RSS: Hutchins et al. (2008) suggest taking the first rank value for which we have an inflection point. Frigyesi et al. (2008) instead consider the first rank value for which the decrease of the RSS on real data is less than the decrease of the RSS on the random data; vi) silhouette values measured on the matrices of the base, of the coefficients and the consensus matrix; vii) trend of the sparseness introduced by Hoyer (2004). B) Multiple consensus maps corresponding to different value of k. Supplementary Figure S8. Heatmap of the most important antibodies in each of the k = 6 metagenes resulting from the model. Supplementary Figure S9. Principal Component Analysis (PCA) algorithm applied to Elesclomol data, whereby each cell line is considered as a function of the antibodies. A) Scree plot. Given the low amount of variance explained by the variables above the fifth, we considered up to 5 principal components. B) Biplots using cell lines and growth conditions as scores. Ellipses represent the 95% probability of finding sample score values. Supplementary Figure S10. Principal Component Analysis (PCA) biplots of components of the antibodies using (A) Time and (B) treatment, respectively. Ellipses represent the 95% probability of finding sample score values. Supplementary Figure S11. Concent ration-response assays on all the four selected GSC lines for setting the dose of Elesclomol most suitable for the combination with TMZ.
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- 2021
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22. PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
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Mangiapane, Laura Rosa, Nicotra, Annalisa, Turdo, Alice, Gaggianesi, Miriam, Bianca, Paola, Di Franco, Simone, Sardina, Davide Stefano, Veschi, Veronica, Signore, Michele, Beyes, Sven, Fagnocchi, Luca, Fiori, Micol Eleonora, Bongiorno, Maria Rita, Lo Iacono, Melania, Pillitteri, Irene, Ganduscio, Gloria, Gulotta, Gaspare, Medema, Jan Paul, Zippo, Alessio, Todaro, Matilde, De Maria Marchiano, Ruggero, Stassi, Giorgio, De Maria, Ruggero (ORCID:0000-0003-2255-0583), Mangiapane, Laura Rosa, Nicotra, Annalisa, Turdo, Alice, Gaggianesi, Miriam, Bianca, Paola, Di Franco, Simone, Sardina, Davide Stefano, Veschi, Veronica, Signore, Michele, Beyes, Sven, Fagnocchi, Luca, Fiori, Micol Eleonora, Bongiorno, Maria Rita, Lo Iacono, Melania, Pillitteri, Irene, Ganduscio, Gloria, Gulotta, Gaspare, Medema, Jan Paul, Zippo, Alessio, Todaro, Matilde, De Maria Marchiano, Ruggero, Stassi, Giorgio, and De Maria, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Objective: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy. Design: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance. Results: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy. Conclusions: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting.
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- 2021
23. MOESM11 of A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer
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Francescangeli, Federica, Contavalli, Paola, Angelis, Maria Laura De, Careccia, Silvia, Signore, Michele, Haas, Tobias Longin, Salaris, Federico, Baiocchi, Marta, Boe, Alessandra, Giuliani, Alessandro, Tcheremenskaia, Olga, Pagliuca, Alfredo, Guardiola, Ombretta, Minchiotti, Gabriella, Colace, Lidia, Ciardi, Antonio, D’Andrea, Vito, Torre, Filippo La, JanPaul Medema, Maria, Ruggero De, and Zeuner, Ann
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neoplasms ,health care economics and organizations ,digestive system diseases - Abstract
Additional file 11: Figure S5. ZEB2 expression in TNM stages, correlation with RFS and CMS in stage 2 CRC patients. ZEB2 transcript levels in the indicated number of CRC patients across all TNM stages. One-way ANOVA resulted in non-significant differences between stages. Outliers are depicted as crosses. n = 1079.
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- 2020
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24. Deregulated expression of the imprinted DLK1-DIO3 region in Glioblastoma Stem-like Cells: tumor suppressor role of lncRNA MEG3
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Buccarelli, Mariachiara, Lulli, Valentina, Giuliani, Alessandro, Signore, Michele, Martini, Maurizio, D'Alessandris, Quintino Giorgio, Giannetti, Stefano, Novelli, Agnese, Ilari, Ramona, Giurato, Giorgio, Boe, Alessandra, Castellani, Giorgia, Spartano, Serena, Marangi, Giuseppe, Biffoni, Mauro, Genuardi, Maurizio, Pallini, Roberto, Marziali, Giovanna, Ricci-Vitiani, Lucia, Martini, Maurizio (ORCID:0000-0002-6260-6310), D'Alessandris, Quintino G (ORCID:0000-0002-2953-9291), Giannetti, Stefano (ORCID:0000-0002-9456-8865), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Pallini, Roberto (ORCID:0000-0002-4611-8827), Buccarelli, Mariachiara, Lulli, Valentina, Giuliani, Alessandro, Signore, Michele, Martini, Maurizio, D'Alessandris, Quintino Giorgio, Giannetti, Stefano, Novelli, Agnese, Ilari, Ramona, Giurato, Giorgio, Boe, Alessandra, Castellani, Giorgia, Spartano, Serena, Marangi, Giuseppe, Biffoni, Mauro, Genuardi, Maurizio, Pallini, Roberto, Marziali, Giovanna, Ricci-Vitiani, Lucia, Martini, Maurizio (ORCID:0000-0002-6260-6310), D'Alessandris, Quintino G (ORCID:0000-0002-2953-9291), Giannetti, Stefano (ORCID:0000-0002-9456-8865), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), and Pallini, Roberto (ORCID:0000-0002-4611-8827)
- Abstract
Background: Glioblastoma (GBM) stem-like cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted DLK-DIO3 region on chromosome 14q32 in GBM pathogenesis. Methods: RT-PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression and Reverse-Phase protein Array profiles were used to investigate the tumor suppressor function of MEG3. Results: Loss of expression of genes and non-coding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared to normal brain. This down-regulation is mainly mediated by epigenetic silencing. Kaplan-Meier analysis indicated that low expression of MEG3 and MEG8 lncRNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration and colony formation and decreases in vivo tumor growth reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and Epithelial to Mesenchymal Transition (EMT). Conclusions: In GBM, MEG3 acts as a tumor-suppressor mainly regulating cell adhesion, EMT and cell proliferation, thus providing a potential candidate for novel GBM therapies.
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- 2020
25. Propranolol enhances cell cycle-related gene expression in pressure overloaded hearts
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Musumeci, Marco, Maccari, Sonia, Sestili, Paola, Signore, Michele, Molinari, Paola, Ambrosio, Caterina, Stati, Tonino, Colledge, William H, Grace, Andrew A, Catalano, Liviana, and Marano, Giuseppe
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- 2011
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26. Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3
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Buccarelli, Mariachiara, primary, Lulli, Valentina, additional, Giuliani, Alessandro, additional, Signore, Michele, additional, Martini, Maurizio, additional, D’Alessandris, Quintino G, additional, Giannetti, Stefano, additional, Novelli, Agnese, additional, Ilari, Ramona, additional, Giurato, Giorgio, additional, Boe, Alessandra, additional, Castellani, Giorgia, additional, Spartano, Serena, additional, Marangi, Giuseppe, additional, Biffoni, Mauro, additional, Genuardi, Maurizio, additional, Pallini, Roberto, additional, Marziali, Giovanna, additional, and Ricci-Vitiani, Lucia, additional
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- 2020
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27. 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
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Figure S1. Additional RPPA endpoints. (PDF 89474 kb)
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- 2019
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28. 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
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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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29. 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
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Figure S2. Clonogenic Assay. (PDF 440 kb)
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- 2019
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30. Additional file 7: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and Bonci, Désirée
- Abstract
Figure S6. (A) Freshly dissociated tissues maintained for one week in serum-free stem cell-isolating medium supplemented with Epidermal Growth Factor (EGF), basic Fibroblast Growth Factor (b-FGF), DMEM (Dulbecco Modified Eagle Medium), or Glutamine and FBS (Fetal Bovine Serum) supplemented medium, and analyzed by cytofluorimetric analysis. CD45 (PE-Cy7), CD146 (PE), CD44 (H450-Pacific Blue) and EpCAM (FITC) antigens were analyzed. TOPRO3 was used for gating vital cells. (B) The histograms report growth rate fold change of cells described in A, 4 and 10 days after sorting. Control represents (red dashed line) value = 1 i.e. reference relative count at sorting and plating day. Mean of three independent experiments is reported. Values are mean ± s.d (C) Colony forming assay of EpCAM+/CD146+/CD44+ and triple negative sorted cells and non-sorted population maintained in culture one week in stem serum free medium (D) Mean colony size of EpCAM+/CD146+/CD44+ and triple negative sorted cells and non-sorted population maintained in culture one week in stem serum free medium. Mean of three independent experiments is reported. Values are mean ± s.d. (PDF 231 kb)
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- 2018
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31. Additional file 11: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and Bonci, Désirée
- Abstract
Figure S8. (A) Representative images of Western blot analysis of pAKT S473 and pERK T202/Y204 proteins in clear renal cancer isolated cells (G3 and G4) and commercial lines [primary tumor 786–0 (786) and metastatic Caki-1 (CK1)]. GAPDH expression was used as internal control (B) Anti-mTOR and VEGFR2 protein staining in two representative samples classified by (ISUP) grading as G3 and G4 cases by immunohistochemistry assay. Microscope used Nikon Eclipse 55i, magnification 20X. (C) Representative images of Western blot analysis of pAKT S473 and pERK T202/Y204 proteins in non-sorted stem serum free clear renal cancer enriched cells (Stem Tot.), EpCAM+/CD146+/CD44+ (Stem+) and triple negative (Stem-) sorted cells vs non-sorted clear renal cancer cells maintained in DMEM-FBS condition (DMEM Tot) and evaluated one week after culture. (D) Two-way unsupervised hierarchical clustering of 18 ccRCC samples for the expression of proteins belonging to the angiogenesis pathway. Highlighted in the yellow box are overexpressed protein commonly shared in samples of patients that underwent progression (red arrows). N1 and M1 samples were excluded from the analysis (E) Receiver operating characteristic (ROC) curve showing sensitivity and specificity of HIF-1 alpha and phospho-mTOR (S2448) protein RPPA expressions in predicting progression. The true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity). The area under the ROC curve (AUC) represents a measure of how well the HIF-1 alpha and phospho-mTOR (S2448) protein RPPA expressions distinguishes progression group from no progression [0.96 (p
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- 2018
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32. Additional file 6: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and DĂŠsirĂŠe Bonci
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Figure S5. Freshly dissociated tissues were maintained three days in serum-free stem cell-isolating medium supplemented with Epidermal Growth Factor (EGF) and basic Fibroblast Growth Factor (b-FGF). On the left a representative image of the sorting of EpCAM+/CD146+/CD44+ populations (EpCAM+/CD146+/CD44+) and triple negative (EpCAM-/CD146-/CD44-) by FACS ARIA cytometer was reported. Images of colonies of both sorted sub-populations were reported on the right. Yellow and pink boxes mirror cytometer density plot. Pink dashed line represents matrigel front of cell invasion. (PDF 179 kb)
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- 2018
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33. Additional file 4: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and DĂŠsirĂŠe Bonci
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Figure S3 (A) RPPA-TCGA elaboration of E-Cadherin and Fibronectin expressions. Data were obtained from macrodissected clear cell renal cancer tissues (GDC-database- https://tcga-data.nci.nih.gov/docs/publications/kirc_2013/ ) and reported for grading, stage and for progression rate by RPPA. (B) mRNA level elaboration of EpCAM, CD146(MCAM) and CD44 antigens. Data were obtained from GSE48550 microarray and were analyzed on different kinds of renal stem cells. (C) TOPRO3 staining for cell viability evaluation of populations maintained for three days (upper panels) and one week (Lower panels) in serum-free stem cell-isolating medium supplemented with Epidermal Growth Factor (EGF), basic Fibroblast Growth Factor (b-FGF), DMEM (Dulbecco Modified Eagle Medium), Glutamine and FBS (Fetal Bovine Serum) supplemented medium and evaluated by cytofluorimetric analysis. Blue and Black areas represent vital and dead cells respectively. (PDF 389 kb)
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- 2018
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34. Additional file 8: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and Bonci, Désirée
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Table S2. Clinical features of 20 collected ccRCC patients including: 2 G1; 7 G2; 8 G3 and 3 G4 processed by RPPA. (PDF 488 kb)
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- 2018
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35. Additional file 5: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and DĂŠsirĂŠe Bonci
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Figure S4. (A) Fresh dissociated tissues maintained for three days in serum-free stem cell-isolating medium supplemented with Epidermal Growth Factor (EGF), basic Fibroblast Growth Factor (b-FGF), DMEM (Dulbecco Modified Eagle Medium), or in Glutamine and FBS (Fetal Bovine Serum) supplemented medium, and analyzed by cytofluorimetric analysis. CD45 (PE-Cy7), CD146(PE), CD44 (H450-Pacific Blue) and EpCAM(FITC) antigens were analyzed. TOPRO3 was used for gating vital cells. (B-C) Images and clonogenic population percentage of cells maintained in both conditions after three days of culture by Colony forming assay. Colonies distinguished on the basis of their shape in the two conditions: spheroidal (blue box) and bidimensional (red box). (D) Percentage of colonies distinguished on the basis of their shape in the two conditions was reported: spheroidal (blue box) and bidimentional (red box) such as in B. (PDF 229 kb)
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- 2018
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36. Additional file 9: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and DĂŠsirĂŠe Bonci
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body regions ,nervous system ,mental disorders ,fungi - Abstract
Table S3. List of total and phosphorylated proteins analyzed by RPPA. In blue, positively expressed proteins. (PDF 87 kb)
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- 2018
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37. Additional file 2: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and Bonci, Désirée
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Figure S1. (A) (PANEL1) Table of 1286 ccRCC patient distribution: 1013 tumor free patients at 36 months from surgery, 130 metastatic (M1) patients at diagnosis time and 143 recurrent patients at 36 months after surgery were reported. (PANEL2) Table of 57 ccRCC cancer patient distribution: 37 tumor free patients at 36 months from surgery, 6 metastatic (M1) patients at diagnosis time and 14 recurrent patients at 36 months from surgery were reported. (B) Representative immunofluorescence of DAPI-stained tumor derived spheroids. (C) Representative image of 7- aminoactinomycin D staining (7AAD) of in vitro isolated populations by flow cytometry. (D) Table reporting distribution of specific antigen expression percentages (%) in all studied ccRCC populations. (E) Representative images of flow cytometry analysis showing the expression of the epithelial and undifferentiated cell markers EpCAM, CD24, CD10, CD90, CD44 and CD146 mesenchymal stem cell markers in ccRCC isolated populations. Background staining was calculated by using appropriate isotype controls. (F) Flow cytometry analysis of cell lines 786–0 and Caki-1 representative of primary and metastatic tumor, respectively. One representative staining of three independent experiments is shown. (PDF 243 kb)
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- 2018
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38. Additional file 3: of Renal cancer: new models and approach for personalizing therapy
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Martino, Simona Di, Luca, Gabriele De, Grassi, Ludovica, Federici, Giulia, Alfonsi, Romina, Signore, Michele, Addario, Antonio, Salvo, Laura De, Francescangeli, Federica, Sanchez, Massimo, Tirelli, Valentina, Muto, Giovanni, Sperduti, Isabella, Steno Sentinelli, Costantini, Manuela, Pasquini, Luca, Milella, Michele, Haoui, Mustapha, Simone, Giuseppe, Gallucci, Michele, Maria, Ruggero De, and DĂŠsirĂŠe Bonci
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Figure S2. (A) Hematoxylin and Eosin (H&E) and CD31 staining of formalin-fixed and paraffin- embedded (FPPE) of primary tumors. Three patients for each grading were analyzed. A representative image for samples is reported. (B) RPPA-TCGA elaboration of CD31 expression. Data were obtained from macrodissected clear cell renal cancer tissues (GDC-database- https://tcga-data.nci.nih.gov/docs/publications/kirc_2013/ ) and reported for grading, stage and for progression rate by RPPA. (C) Representative images of flow cytometry analysis showing the expression of the endothelial CD31, VE-Cadherin (VE-Cadh) and putative stem cell markers (CD133, CD105) in ccRCC isolated populations. The analysis was combined with CD44 expression. Background staining was calculated by using appropriate isotype controls. (PDF 402 kb)
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- 2018
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39. Gut Mesenchymal Stromal Cells in Immunity
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Messina, Valeria, Buccione, Carla, Marotta, Giulia, Ziccheddu, Giovanna, Signore, Michele, Mattia, Gianfranco, Puglisi, Rossella, Sacchetti, Benedetto, Biancone, Livia, and Valtieri, Mauro
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Article Subject - Abstract
Mesenchymal stromal cells (MSCs), first found in bone marrow (BM), are the structural architects of all organs, participating in most biological functions. MSCs possess tissue-specific signatures that allow their discrimination according to their origin and location. Among their multiple functions, MSCs closely interact with immune cells, orchestrating their activity to maintain overall homeostasis. The phenotype of tissue MSCs residing in the bowel overlaps with myofibroblasts, lining the bottom walls of intestinal crypts (pericryptal) or interspersed within intestinal submucosa (intercryptal). In Crohn’s disease, intestinal MSCs are tightly stacked in a chronic inflammatory milieu, which causes their enforced expression of Class II major histocompatibility complex (MHC). The absence of Class II MHC is a hallmark for immune-modulator and tolerogenic properties of normal MSCs and, vice versa, the expression of HLA-DR is peculiar to antigen presenting cells, that is, immune-activator cells. Interferon gamma (IFNγ) is responsible for induction of Class II MHC expression on intestinal MSCs. The reversal of myofibroblasts/MSCs from an immune-modulator to an activator phenotype in Crohn’s disease results in the formation of a fibrotic tube subverting the intestinal structure. Epithelial metaplastic areas in this context can progress to dysplasia and cancer.
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- 2017
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40. The Double Face of Exosome-Carried MicroRNAs in Cancer Immunomodulation
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Alfonsi, Romina, primary, Grassi, Ludovica, additional, Signore, Michele, additional, and Bonci, Désirée, additional
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- 2018
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41. Drug repurposing for the treatment of glioblastoma multiforme
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Abbruzzese, Claudia, primary, Matteoni, Silvia, additional, Signore, Michele, additional, Cardone, Luca, additional, Nath, Kavindra, additional, Glickson, Jerry D., additional, and Paggi, Marco G., additional
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- 2017
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42. The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response
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D'Alessandris, Quintino Giorgio, Biffoni, Mauro, Martini, Maurizio, Runci, Daniele, Buccarelli, Mariachiara, Cenci, Tonia, Signore, Michele, Stancato, Loui, Olivi, Alessandro, De Maria Marchiano, Ruggero, Larocca, Luigi M., Ricci-Vitiani, Lucia, Pallini, Roberto, D'Alessandris, Quintino Giorgio (ORCID:0000-0002-2953-9291), Martini, Maurizio (ORCID:0000-0002-6260-6310), Olivi, Alessandro (ORCID:0000-0002-4489-7564), De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Larocca, Luigi M. (ORCID:0000-0003-1739-4758), Pallini, Roberto (ORCID:0000-0002-4611-8827), D'Alessandris, Quintino Giorgio, Biffoni, Mauro, Martini, Maurizio, Runci, Daniele, Buccarelli, Mariachiara, Cenci, Tonia, Signore, Michele, Stancato, Loui, Olivi, Alessandro, De Maria Marchiano, Ruggero, Larocca, Luigi M., Ricci-Vitiani, Lucia, Pallini, Roberto, D'Alessandris, Quintino Giorgio (ORCID:0000-0002-2953-9291), Martini, Maurizio (ORCID:0000-0002-6260-6310), Olivi, Alessandro (ORCID:0000-0002-4489-7564), De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Larocca, Luigi M. (ORCID:0000-0003-1739-4758), and Pallini, Roberto (ORCID:0000-0002-4611-8827)
- Abstract
Background. Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods. The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 Î1⁄4M to 1 mM) was related with patients' survival. Results. Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 Î1⁄4M, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions. Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.
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- 2017
43. Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
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Haas, Tobias Longin, Sciuto, Maria Rita, Brunetto, Lidia, Valvo, Cecilia, Signore, Michele, Fiori, Micol Eleonora, di Martino, Simona, Giannetti, Stefano, Morgante, Liliana, Boe, Alessandra, Patrizii, Michele, Warnken, Uwe, Schnölzer, Martina, Ciolfi, Andrea, Di Stefano, Chiara, Biffoni, Mauro, Ricci-Vitiani, Lucia, Pallini, Roberto, De Maria Marchiano, Ruggero, Haas, Tobias L. (ORCID:0000-0003-2336-0263), Fiori, Micol E., Giannetti, Stefano (ORCID:0000-0002-9456-8865), Pallini, Roberto (ORCID:0000-0002-4611-8827), De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Haas, Tobias Longin, Sciuto, Maria Rita, Brunetto, Lidia, Valvo, Cecilia, Signore, Michele, Fiori, Micol Eleonora, di Martino, Simona, Giannetti, Stefano, Morgante, Liliana, Boe, Alessandra, Patrizii, Michele, Warnken, Uwe, Schnölzer, Martina, Ciolfi, Andrea, Di Stefano, Chiara, Biffoni, Mauro, Ricci-Vitiani, Lucia, Pallini, Roberto, De Maria Marchiano, Ruggero, Haas, Tobias L. (ORCID:0000-0003-2336-0263), Fiori, Micol E., Giannetti, Stefano (ORCID:0000-0002-9456-8865), Pallini, Roberto (ORCID:0000-0002-4611-8827), and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target. Haas et al. identify integrin α7 as a functional marker of glioblastoma stem cells by screening a monoclonal antibody library generated against primary glioblastoma (GBM) cells. Functional experiments in culture and in vivo show that the targeting of integrin α7 has potential as a therapeutic avenue for treating this aggressive disease.
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- 2017
44. Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
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Haas, Tobias L., primary, Sciuto, Maria Rita, additional, Brunetto, Lidia, additional, Valvo, Cecilia, additional, Signore, Michele, additional, Fiori, Micol E., additional, di Martino, Simona, additional, Giannetti, Stefano, additional, Morgante, Liliana, additional, Boe, Alessandra, additional, Patrizii, Michele, additional, Warnken, Uwe, additional, Schnölzer, Martina, additional, Ciolfi, Andrea, additional, Di Stefano, Chiara, additional, Biffoni, Mauro, additional, Ricci-Vitiani, Lucia, additional, Pallini, Roberto, additional, and De Maria, Ruggero, additional
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- 2017
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45. Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread
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Spreafico, Filippo, primary, Bongarzone, Italia, additional, Pizzamiglio, Sara, additional, Magni, Ruben, additional, Taverna, Elena, additional, De Bortoli, Maida, additional, Ciniselli, Chiara M., additional, Barzanò, Elena, additional, Biassoni, Veronica, additional, Luchini, Alessandra, additional, Liotta, Lance A., additional, Zhou, Weidong, additional, Signore, Michele, additional, Verderio, Paolo, additional, and Massimino, Maura, additional
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- 2017
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46. Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors
- Author
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Pizzamiglio, Sara, primary, De Bortoli, Maida, additional, Taverna, Elena, additional, Signore, Michele, additional, Veneroni, Silvia, additional, Cho, William, additional, Orlandi, Rosaria, additional, Verderio, Paolo, additional, and Bongarzone, Italia, additional
- Published
- 2017
- Full Text
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47. The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response
- Author
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D’Alessandris, Quintino Giorgio, primary, Biffoni, Mauro, additional, Martini, Maurizio, additional, Runci, Daniele, additional, Buccarelli, Mariachiara, additional, Cenci, Tonia, additional, Signore, Michele, additional, Stancato, Louis, additional, Olivi, Alessandro, additional, De Maria, Ruggero, additional, Larocca, Luigi M., additional, Ricci-Vitiani, Lucia, additional, and Pallini, Roberto, additional
- Published
- 2017
- Full Text
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48. Altered Traffic of Cardiolipin during Apoptosis: Exposure on the Cell Surface as a Trigger for 'Antiphospholipid Antibodies'
- Author
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Manganelli, Valeria, Capozzi, Antonella, Recalchi, Serena, Signore, Michele, Mattei, Vincenzo, Garofalo, Tina, Misasi, Roberta, Degli Esposti, Mauro, and Sorice, Maurizio
- Subjects
Article Subject - Abstract
Apoptosis has been reported to induce changes in the remodelling of membrane lipids; after death receptor engagement, specific changes of lipid composition occur not only at the plasma membrane, but also in intracellular membranes. This paper focuses on one important aspect of apoptotic changes in cellular lipids, namely, the redistribution of the mitochondria-specific phospholipid, cardiolipin (CL). CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles. After death receptor stimulation, CL appears to concentrate into mitochondrial “raft-like” microdomains at contact sites between inner and outer mitochondrial membranes, leading to local oligomerization of proapoptotic proteins, including Bid. Clustering of Bid in CL-enriched contacts sites is interconnected with pathways of CL remodelling that intersect membrane traffic routes dependent upon actin. In addition, CL association with cytoskeleton protein vimentin was observed. Such novel association also indicated that CL molecules may be expressed at the cell surface following apoptotic stimuli. This observation adds a novel implication of biomedical relevance. The association of CL with vimentin at the cell surface may represent a “new” target antigen in the context of the apoptotic origin of anti-vimentin/CL autoantibodies in Antiphospholipid Syndrome.
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- 2015
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49. Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance
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De Angelis, Maria Laura, Zeuner, Ann, Policicchio, Eleonora, Russo, Giorgio, Bruselles, Alessandro, Signore, Michele, Vitale, Sara, De Luca, Gabriele, Pilozzi, Emanuela, Boe, Alessandra, Stassi, Giorgio, Ricci Vitiani, Lucia, Amoreo, Carla Azzurra, Pagliuca, Alfredo, Francescangeli, Federica, Tartaglia, Marco, De Maria Marchiano, Ruggero, Baiocchi, Marta, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), De Angelis, Maria Laura, Zeuner, Ann, Policicchio, Eleonora, Russo, Giorgio, Bruselles, Alessandro, Signore, Michele, Vitale, Sara, De Luca, Gabriele, Pilozzi, Emanuela, Boe, Alessandra, Stassi, Giorgio, Ricci Vitiani, Lucia, Amoreo, Carla Azzurra, Pagliuca, Alfredo, Francescangeli, Federica, Tartaglia, Marco, De Maria Marchiano, Ruggero, Baiocchi, Marta, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents.Wepropose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance.
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- 2016
50. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells
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Lugini, Luana, primary, Valtieri, Mauro, additional, Federici, Cristina, additional, Cecchetti, Serena, additional, Meschini, Stefania, additional, Condello, Maria, additional, Signore, Michele, additional, and Fais, Stefano, additional
- Published
- 2016
- Full Text
- View/download PDF
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