The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Elena Cetti - One of the best experts on this subject based on the ideXlab platform.
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Mitosis perturbation by MASTL depletion impairs the viability of Thyroid Tumor cells.
Cancer letters, 2018Co-Authors: Elena Cetti, Tiziana Di Marco, Daniele Lecis, Giuseppe Mauro, Sonia Pagliardini, Mara Mazzoni, Emanuela Minna, Lucia Gioiosa, Silvia Brich, Maria Grazia BorrelloAbstract:Even if Thyroid Tumors are generally curable, a fraction will develop resistance to therapy and progress towards undifferentiated forms, whose treatment remains a demanding challenge. To identify potential novel targets for treatment of Thyroid cancer, in a previous study using siRNA-mediated functional screening, we identified several genes that are essential for the growth of Thyroid Tumor, but not normal cells. Among the top-ranking hits, we found microtubule associated serine/threonine kinase-like (MASTL), which is known to play an essential role in mitosis regulation, and is also involved in the DNA damage response. Herein, we examine the effects of MASTL depletion on growth and viability of Thyroid Tumor cells. MASTL depletion impaired cell proliferation and increased the percentage of cells presenting nuclear anomalies, which are indicative of mitotic catastrophe. Furthermore, MASTL depletion was associated with enhanced DNA damage. All these effects eventually led to cell death, characterized by the presence of apoptotic markers. Moreover, MASTL depletion sensitized Thyroid Tumor cells to cisplatin. Our results demonstrate that MASTL represents vulnerability for Thyroid Tumor cells, which could be explored as a therapeutic target for Thyroid cancer.
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identification and characterization of potential novel targets in Thyroid carcinoma evidence of non oncogene addiction unveiling Tumor cell vulnerabilities
2017Co-Authors: Elena CettiAbstract:Thyroid cancer is the most frequent endocrine malignancy, with an incidence constantly increasing. Despite well-differentiated Thyroid Tumors are generally cured by conventional therapy, a fraction of them relapses and progresses towards undifferentiated forms, characterized by a poor prognosis. Target therapies introduced in clinical testing are often unsuccessful; therefore, novel therapeutic strategies are needed. To identify critical nodal points for therapeutic intervention, our laboratory faced the “non-oncogene addiction” (NOA) paradigm, which asserts that the Tumorigenic state relies on the activity of genes that are essential to support the phenotype of cancer cells but not required to the same degree for normal cell viability. By screening a siRNA library on normal and Tumor Thyroid cell lines, we identified 15 genes whose silencing interfered with the growth of Tumor but not normal Thyroid cells. The overall aim of this project was to validate NOA genes to identify Thyroid Tumor cell vulnerabilities and to explore their role in the regulation of Thyroid Tumor cell biology. Among the 15 hit genes, we selected MASTL, Cyclin D1 and COPZ1 for validation studies. We confirmed the growth inhibitory effect of their silencing in Tumor but not normal Thyroid cells and observed that these effects were common to a panel of Thyroid Tumor cell lines, irrespective of the histotype or genetic lesion. Functional studies on MASTL demonstrated that its depletion in Thyroid Tumor cells inhibited cell growth, led to mitotic catastrophe and induced DNA damage and cell death. COPZ1 depletion induced abortive autophagy, endoplasmic reticulum stress and apoptotic cell death in Thyroid Tumor cells, as well as Tumor growth inhibition in vivo. Together, our studies identified MASTL and COPZ1 as vulnerability genes for Thyroid Tumor cells and provided the rationale for future studies aimed to explore their targeting for potential therapeutic intervention.
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targeting copz1 non oncogene addiction counteracts the viability of Thyroid Tumor cells
Cancer Letters, 2017Co-Authors: Maria Chiara Anania, Tiziana Di Marco, Elena Cetti, Daniele Lecis, Alessandro Gulino, Giuseppe Mauro, Sonia Pagliardini, Katia Todoerti, Loredana Cleris, Giacomo ManentiAbstract:Abstract Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this Tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to Thyroid Tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse Tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of Tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of Thyroid Tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for Thyroid cancer.
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Identification of Thyroid Tumor cell vulnerabilities through a siRNA-based functional screening
Oncotarget, 2015Co-Authors: Maria Chiara Anania, Elena Cetti, Katia Todoerti, Mara Mazzoni, Fabio Gasparri, Ivan Fraietta, Claudia Miranda, Riccardo Colombo, G UkmarAbstract:The incidence of Thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of Thyroid Tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for Thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in Thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3–1). We identified a panel of hit genes whose silencing interferes with the growth of Tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for Thyroid Tumor cells, as their inhibition reduced the viability of several Thyroid Tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of Thyroid Tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies.
Maria Chiara Anania - One of the best experts on this subject based on the ideXlab platform.
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targeting copz1 non oncogene addiction counteracts the viability of Thyroid Tumor cells
Cancer Letters, 2017Co-Authors: Maria Chiara Anania, Tiziana Di Marco, Elena Cetti, Daniele Lecis, Alessandro Gulino, Giuseppe Mauro, Sonia Pagliardini, Katia Todoerti, Loredana Cleris, Giacomo ManentiAbstract:Abstract Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this Tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to Thyroid Tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse Tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of Tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of Thyroid Tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for Thyroid cancer.
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Identification of Thyroid Tumor cell vulnerabilities through a siRNA-based functional screening
Oncotarget, 2015Co-Authors: Maria Chiara Anania, Elena Cetti, Katia Todoerti, Mara Mazzoni, Fabio Gasparri, Ivan Fraietta, Claudia Miranda, Riccardo Colombo, G UkmarAbstract:The incidence of Thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of Thyroid Tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for Thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in Thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3–1). We identified a panel of hit genes whose silencing interferes with the growth of Tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for Thyroid Tumor cells, as their inhibition reduced the viability of several Thyroid Tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of Thyroid Tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies.
Monica Fedele - One of the best experts on this subject based on the ideXlab platform.
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HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human Thyroid carcinomas
Oncogene, 2008Co-Authors: J Martinez Hoyos, Monica Fedele, Angelo Ferraro, Silvana Sacchetti, Simona Keller, I De Martino, Eleonora Borbone, Pierlorenzo Pallante, Donatella Montanaro, Francesco EspositoAbstract:HMGA1 proteins exert their major physiological function during embryonic development and play a critical role in neoplastic transformation. Here, we show that Hand1 gene, which codes for a transcription factor crucial for differentiation of trophoblast giant cells and heart development, is upregulated in hmga1 minus embryonic stem cells. We demonstrate that HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity. We have also investigated HAND1 expression in human Thyroid carcinoma cell lines and tissues, in which HMGA proteins are overexpressed, with respect to normal Thyroid; an inverse correlation between HMGA1 and HAND1 expression was found in all Thyroid Tumor histotypes. A correlation between HAND1 gene repression and promoter hypermethylation was found in anaplastic carcinomas but not in other Thyroid Tumor histotypes. Therefore, we can hypothesize that HMGA1 overexpression plays a key role on HAND1 silencing in differentiated Thyroid carcinomas and that promoter hypermethylation occurs in later stages of Thyroid Tumor progression. Finally, the restoration of the HAND1 gene expression reduces the clonogenic ability of two human Thyroid carcinoma-derived cell lines, suggesting that HAND1 downregulation may have a role in the process of Thyroid carcinogenesis.
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Status and expression of the p16INK4 gene in human Thyroid Tumors and Thyroid-Tumor cell lines.
International journal of cancer, 1996Co-Authors: Viola Calabrò, Maria Strazzullo, Girolama La Mantia, Monica Fedele, Christian Paulin, Alfredo Fusco, Luigi LaniaAbstract:The p16INK4 Tumor-suppressor gene (also known as CDKN2, CDK41 and MTSI) encodes a negative regulator of the cell cycle. This gene, located in 9p21, is mutated or homozygously deleted in a high percentage of Tumor cell lines and specific types of primary Tumors. We have examined the status of the p16INK4 gene in 31 Thyroid Tumors and 7 Thyroid cell lines. No DNA abnormalities were found in primary Tumors. Conversely, p16INK4 gene structural alterations, deletions and point mutations were found in 4 Thyroid cell lines. The expression of the 2 different p16INK4 mRNAs, the p16α and p16β transcripts, was determined by RNA-PCR experiments. All the primary Thyroid Tumors expressed the β transcript, while the p16α was barely detectable. The Thyroid cell lines always expressed the p16β transcript, while the α transcript was absent or, whenever present, coded for a mutated form of the p16INK4 gene product. Taken together, our results suggest that loss of p16INK4 function is not directly involved in the process of Thyroid-Tumor development, but it probably gives cells in tissue culture a selective growth advantage. © 1996 Wiley-Liss, Inc.
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upregulation of vascular endothelial growth factor vegf and downregulation of placenta growth factor plgf associated with malignancy in human Thyroid Tumors and cell lines
Oncogene, 1995Co-Authors: Giuseppe Viglietto, Monica Fedele, Domenico Maglione, M Rambaldi, J Cerutti, Annunciata Romano, Francesco Trapasso, P Ippolito, Gennaro Chiappetta, Gerardo BottiAbstract:Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells in vitro, promotes neoangiogenesis in vivo and increases the permeability of the vascular endothelium. VEGF overexpression occurs in several cultured Tumor cell lines and in certain human malignancies. Placenta growth factor (PlGF) is a recently identified growth factor for endothelial cells (EC); PlGF strongly potentiates both the proliferative and the permeabilization effects exerted by VEGF on the vascular endothelium. To uncover the molecular mechanisms underlying neoangiogenesis in human Thyroid Tumors, we have analysed VEGF and PlGF expression in a panel of Thyroid carcinoma cell lines with different Tumorigenic potential as well as in human primary Thyroid Tumors. We show that a high Tumorigenic potential is associated with an elevated VEGF expression in human Thyroid Tumor cell lines. Furthermore, VEGF overexpression occurs in 5/5 highly malignant anaplastic carcinomas. Papillary and follicular carcinomas express intermediate levels of VEGF mRNA. In contrast, PlGF expression is severely down regulated in the majority of Thyroid Tumor cell lines and in Tumors. Furthermore, we show that both the VEGF receptors, FLT-1 and flk/KDR, are expressed in endothelial cells that line Tumor-embedded microvascular vessels, suggesting that VEGF but not PlGF, contributes to Thyroid Tumor development.
Katia Todoerti - One of the best experts on this subject based on the ideXlab platform.
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COPZ1 depletion in Thyroid Tumor cells triggers type I IFN response and immunogenic cell death
'Elsevier BV', 2020Co-Authors: T. Di Marco, Sonia Pagliardini, Katia Todoerti, F. Bianchi, L. Sfondrini, I. Bongarzone, E.m. Maffioli, G. Tedeschi, M. Mazzoni, S. PellegriniAbstract:The coatomer protein complex zeta 1 (COPZ1) represents a non-oncogene addiction for Thyroid cancer (TC); its depletion impairs the viability of Thyroid Tumor cells, leads to abortive autophagy, ER stress, UPR and apoptosis, and reduces Tumor growth of TC xenograft models. In this study we investigated the molecular pathways activated by COPZ1 depletion and the paracrine effects on cellular microenvironment and immune response. By comprehensive and target approaches we demonstrated that COPZ1 depletion in TPC-1 and 8505C Thyroid Tumor cell lines activates type I IFN pathway and viral mimicry responses. The secretome from COPZ1 depleted cells was enriched for several inflammatory molecules and damage-associated molecular patterns (DAMPs). Moreover, we found that dendritic cells, exposed to these secretomes, expressed high levels of differentiation and maturation markers, and stimulated the proliferation of na\uefve T cells. Interestingly, T cells stimulated with COPZ1-depleted cells showed increased cytotoxic activity against parental Tumor cells. Collectively, our findings support the notion that targeting COPZ1 may represent a promising therapeutic approach for TC, considering its specificity for cancer cells, the lack of effect on normal cells, and the capacity to prompt an anti-Tumor immune response
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targeting copz1 non oncogene addiction counteracts the viability of Thyroid Tumor cells
Cancer Letters, 2017Co-Authors: Maria Chiara Anania, Tiziana Di Marco, Elena Cetti, Daniele Lecis, Alessandro Gulino, Giuseppe Mauro, Sonia Pagliardini, Katia Todoerti, Loredana Cleris, Giacomo ManentiAbstract:Abstract Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this Tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to Thyroid Tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse Tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of Tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of Thyroid Tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for Thyroid cancer.
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Identification of Thyroid Tumor cell vulnerabilities through a siRNA-based functional screening
Oncotarget, 2015Co-Authors: Maria Chiara Anania, Elena Cetti, Katia Todoerti, Mara Mazzoni, Fabio Gasparri, Ivan Fraietta, Claudia Miranda, Riccardo Colombo, G UkmarAbstract:The incidence of Thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of Thyroid Tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for Thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of Thyroid Tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in Thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3–1). We identified a panel of hit genes whose silencing interferes with the growth of Tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for Thyroid Tumor cells, as their inhibition reduced the viability of several Thyroid Tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of Thyroid Tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies.
Gerardo Botti - One of the best experts on this subject based on the ideXlab platform.
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upregulation of vascular endothelial growth factor vegf and downregulation of placenta growth factor plgf associated with malignancy in human Thyroid Tumors and cell lines
Oncogene, 1995Co-Authors: Giuseppe Viglietto, Monica Fedele, Domenico Maglione, M Rambaldi, J Cerutti, Annunciata Romano, Francesco Trapasso, P Ippolito, Gennaro Chiappetta, Gerardo BottiAbstract:Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells in vitro, promotes neoangiogenesis in vivo and increases the permeability of the vascular endothelium. VEGF overexpression occurs in several cultured Tumor cell lines and in certain human malignancies. Placenta growth factor (PlGF) is a recently identified growth factor for endothelial cells (EC); PlGF strongly potentiates both the proliferative and the permeabilization effects exerted by VEGF on the vascular endothelium. To uncover the molecular mechanisms underlying neoangiogenesis in human Thyroid Tumors, we have analysed VEGF and PlGF expression in a panel of Thyroid carcinoma cell lines with different Tumorigenic potential as well as in human primary Thyroid Tumors. We show that a high Tumorigenic potential is associated with an elevated VEGF expression in human Thyroid Tumor cell lines. Furthermore, VEGF overexpression occurs in 5/5 highly malignant anaplastic carcinomas. Papillary and follicular carcinomas express intermediate levels of VEGF mRNA. In contrast, PlGF expression is severely down regulated in the majority of Thyroid Tumor cell lines and in Tumors. Furthermore, we show that both the VEGF receptors, FLT-1 and flk/KDR, are expressed in endothelial cells that line Tumor-embedded microvascular vessels, suggesting that VEGF but not PlGF, contributes to Thyroid Tumor development.