Researcher:
Şeker-Polat, Fidan

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PhD Student

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Fidan

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Şeker-Polat

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Şeker-Polat, Fidan

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2016 - 201952020 - 20226

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Now showing 1 - 10 of 11
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    Identification of novel molecular players of GBM cell dispersal through an in vitro profiling approach
    (Oxford Univ Press, 2016) Gümüş, Zeynep Hülya; N/A; N/A; N/A; N/A; Department of Industrial Engineering; N/A; Şeker-Polat, Fidan; Erkent, Mahmut Alp; Ergüder, Nazlı; Sevinç, Kenan; Gönen, Mehmet; Önder, Tuğba Bağcı; Phd Student; Undergraduate Student; Undergraduate Student; Phd Student; Faculty Member; Faculty Member; Department of Industrial Engineering; Graduate School of Health Sciences; School of Medicine; School of Medicine; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; N/A; N/A; N/A; N/A; 237468; 184359
    Glioblastoma multiforme (GBM) is the most common and aggressive type of gliomas with a mean survival of 1 year after diagnosis. A major obstacle in treating GBMs is extensive tumor cell infiltration into the surrounding brain. Despite tumor resection and combined therapy, recurrence occurs in the vicinity of the resection margin due to individual cells that dispersed out of the primary tumor, therefore; developing novel therapies that target tumor cell dispersal is of high priority. The goal of this project is to identify genes that are differentially regulated during GBM cell dispersal and to validate their function in in vitro models of dispersal. In this project, we have used an in vitro model of cell motility whereby the dynamics of GBM cell dispersal can be monitored in real-time and quantitated. Accordingly, we isolated motile/migratory/dispersive cells from non-motile/core cells and used these cells for investigating the genes that are differentially regulated during different phases of cell movement by using RNA sequencing. Analysis of the sequencing experiments showed the presence of many differentially expressed genes in motile vs non-motile cells. Most of the genes that have the highest expression in motile cells compared to non-motile ones were linked to epithelial to mesenchymal transition and cell motility based on our pathway and gene set enrichment analyses. Our current focus is on five different candidate genes: CTGF, CYR61, SERPINE1, INHBA and PTX3. Among these, the expression of SERPINE1, a serine protease inhibitor, had predictive value for overall survival of gliomas and therefore is an interesting therapeutic candidate. Currently, we are conducting loss-of-function and gain-of function experiments targeting these genes. Together, these studies have the potential to discover novel molecular players of GBM cell dispersal and open up new avenues for designing new therapeutic strategies against the invasive phenotype of otherwise untreatable malignant GBMs.
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    Combination of epigenetic enzyme inhibitors, gsk-j4 and belinostat, reveals high efficacy in idh1 mutant gliomas
    (N/A, 2020) Wakimoto, Hiroaki; Cahill, Daniel; Cribbs, Adam; Oppermann, Udo; N/A; Kayabölen, Alişan; Şahin, Gizem Nur; Şeker-Polat, Fidan; Cingöz, Ahmet; Işık, Bekir; Acar, Simge; Solaroğlu, İhsan; Önder, Tuğba Bağcı; PhD Student; PhD Student; PhD Student; Researcher; Undergraduate Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; 102059; 184359
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    TRAIL-conjugated silver nanoparticles sensitize glioblastoma cells to TRAIL by regulating CHK1 in the DNA repair pathway
    (Taylor & Francis, 2020) Altunbek, Mine; Kahraman, Mehmet; Culha, Mustafa; Sur, İlknur Erdem; Muslu, Kerem; Değirmenci, Nareg Pınarbaşı; Şeker-Polat, Fidan; Cingöz, Ahmet; Aydın, Serdar Onur; Solaroğlu, İhsan; Önder, Tuğba Bağcı; Faculty Member; Undergraduate Student; PhD Student; PhD Student; Researcher; Researcher; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; 361035; N/A; N/A; 321731; N/A; 102059; 184359
    Objectives: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in cancer cells, but not in normal cells. Resistance of glioblastoma cells to TRAIL is a major obstacle for successful clinical treatment of TRAIL. Thus, there is an essential requirement for novel approaches to sensitize TRAIL resistance. Silver nanoparticles (AgNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AgNPs on TRAIL sensitivity in cancer cells remain unclear. Therefore, we hypothesized that TRAIL-conjugated AgNPs (TRAIL-AgNPs) can overcome TRAIL resistance through inducing death receptor activation in glioblastoma cells, but not normal cells. Methods: In this study, the therapeutic effect of TRAIL-AgNPs is investigated by analyzing the cell viability, caspase activity, and CHK1 gene expression in T98 G TRAIL-Sensitive (TS) and T98 G TRAIL-Resistant (TR) glioblastoma cells. Results: It is found that TRAIL-AgNPs are more toxic compared to TRAIL and AgNPs treatments alone on TR cells. While TRAIL and AgNPs alone do not enhance the caspase activity, conjugation of TRAIL to AgNPs increases the caspase activity in TR cells. Moreover, the TRAIL-AgNPs-treated TR cells show less CHK1 expression compared to the TRAIL treatment. Conclusion: These results suggest that TRAIL sensitivity of TR cells can be enhanced by conjugation of TRAIL with AgNPs, which would be a novel therapeutic approach to sensitize TRAIL resistance.
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    Gelatin methacryloyl hydrogels in the absence of a crosslinker as 3D glioblastoma multiforme (GBM)-mimetic microenvironment
    (Wiley-V C H Verlag Gmbh, 2018) N/A; N/A; N/A; N/A; Department of Chemical and Biological Engineering; Erkoç, Pelin; Şeker-Polat, Fidan; Önder, Tuğba Bağcı; Kızılel, Seda; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; N/A; N/A; 184359; 28376
    3D platforms are important for monitoring tumor progression and screening drug candidates to eradicate tumors such as glioblastoma multiforme (GBM), a malignant type of human brain tumor. Here, a new strategy is reported that exploits visible-light-induced crosslinking of gelatin where the reaction is carried out in the absence of an additional crosslinker. Visible light-induced crosslinking promotes the design of cancer microenvironment-mimetic system without compromising the cell viability during the process and absence of crosslinker facilitates the synthesis of the unique construct. Suspension and spheroid-based models of GBM are used to investigate cellular behavior, expression profiles of malignancy, and apoptosis-related genes within this unique network. Furthermore, sensitivity to an anticancer drug, Digitoxigenin, treatment is investigated in detail. The data suggest that U373 cells, in sparse or spheroid form, have significantly decreased expressions of apoptosis-activating genes, Bad, Puma, and Caspase-3, and a high expression of prosurvival Bcl-2 gene within GelMA hydrogels. Matrix-metalloproteinase genes are also upregulated within GelMA, suggesting positive contribution of gels on extracellular remodeling of cancer cells. This unique photocurable gelatin holds great potential for clinical translation of cancer research through the analysis of 3D malignant cancer cell behavior, and hence for more efficient treatment methods for GBM.
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    Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization
    (Springernature, 2021) Esai Selvan, Myvizhi; Bhere, Deepak; Shah, Khalid; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Cingöz, Ahmet; Özyerli, Ezgi; Morova, Tunç; Şeker-Polat, Fidan; Gümüş, Zeynep Hülya; Solaroğlu, İhsan; Önder, Tuğba Bağcı; Researcher; PhD Student; Master Student; PhD Student; Other; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; 102059; 184359
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell-specific apoptosis, making it a prime therapeutic candidate. However, many tumor cells are either innately TRAIL-resistant, or they acquire resistance with adaptive mechanisms that remain poorly understood. In this study, we generated acquired TRAIL resistance models using multiple glioblastoma (GBM) cell lines to assess the molecular alterations in the TRAIL-resistant state. We selected TRAIL-resistant cells through chronic and long-term TRAIL exposure and noted that they showed persistent resistance both in vitro and in vivo. Among known TRAIL-sensitizers, proteosome inhibitor Bortezomib, but not HDAC inhibitor MS-275, was effective in overcoming resistance in all cell models. This was partly achieved through upregulating death receptors and pro-apoptotic proteins, and downregulating major anti-apoptotic members, Bcl-2 and Bcl-xL. We showed that CRISPR/Cas9 mediated silencing of DR5 could block Bortezomib-mediated re-sensitization, demonstrating its critical role. While overexpression of Bcl-2 or Bcl-xL was sufficient to confer resistance to TRAIL-sensitive cells, it failed to override Bortezomib-mediated re-sensitization. With RNA sequencing in multiple paired TRAIL-sensitive and TRAIL-resistant cells, we identified major alterations in inflammatory signaling, particularly in the NF-kappa B pathway. Inhibiting NF-kappa B substantially sensitized the most resistant cells to TRAIL, however, the sensitization effect was not as great as what was observed with Bortezomib. Together, our findings provide new models of acquired TRAIL resistance, which will provide essential tools to gain further insight into the heterogeneous therapy responses within GBM tumors. Additionally, these findings emphasize the critical importance of combining proteasome inhibitors and pro-apoptotic ligands to overcome acquired resistance.
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    Tumor cell infiltration into the brain in glioblastoma: from mechanisms to clinical perspectives
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Department of Molecular Biology and Genetics; Önder, Tuğba Bağcı; Değirmenci, Nareg Pınarbaşı; Solaroğlu, İhsan; Şeker-Polat, Fidan; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 184359; N/A; 102059; N/A
    Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.
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    PublicationOpen Access
    Parameters influencing gene delivery efficiency of PEGylated chitosan nanoparticles: experimental and modeling approach
    (Wiley, 2022) Bozüyük, Uğur; Erkoç, Pelin; Karacakol, Alp Can; Department of Chemical and Biological Engineering; Department of Mechanical Engineering; Kızılel, Seda; Sitti, Metin; Önder, Tuğba Bağcı; Doğan, Nihal Olcay; Cingöz, Ahmet; Şeker-Polat, Fidan; Nazeer, Muhammad Anwaar; Faculty Member; Faculty Member; PhD Student; PhD Student; Department of Chemical and Biological Engineering; Department of Mechanical Engineering; College of Engineering; School of Medicine; 28376; 297104; 184359; N/A; N/A; N/A; N/A
    Experimentation of nanomedicine is labor-intensive, time-consuming, and requires costly laboratory consumables. Constructing a reliable mathematical model for such systems is also challenging due to the difficulties in gathering a sufficient number of data points. Artificial neural networks (ANNs) are indicated as an efficient approach in nanomedicine to investigate the cause-effect relationships and predict output variables. Herein, an ANN is adapted into plasmid DNA (pDNA) encapsulated and PEGylated chitosan nanoparticles cross-linked with sodium tripolyphosphate (TPP) to investigate the effects of critical parameters on the transfection efficiencies of nanoparticles. The ANN model is developed based on experimental results with three independent input variables: 1) polyethylene glycol (PEG) molecular weight, 2) PEG concentration, and 3) nanoparticle concentration, along with one output variable as a percentage of green fluorescent protein (GFP) expression, which refers to transfection efficiency. The constructed model is further validated with the leave-p-out cross-validation method. The results indicate that the developed model has good prediction capability and is influential in capturing the transfection efficiencies of different nanoparticle groups. Overall, this study reveals that the ANN could be an efficient tool for nanoparticle-mediated gene delivery systems to investigate the impacts of critical parameters in detail with reduced experimental effort and cost.
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    PublicationOpen Access
    Identification of SERPINE1 as a regulator of glioblastoma cell dispersal with transcriptome profiling
    (Multidisciplinary Digital Publishing Institute (MDPI), 2019) Uyulur, Fırat; Selvan, Myvizhi Esa; Gümüş, Zeynep Hülya; Bayraktar, Halil; Wakimoto, Hiroaki; Department of Industrial Engineering; Şeker-Polat, Fidan; Cingöz, Ahmet; Sur, İlknur Erdem; Ergüder, Nazlı; Erkent, Mahmut Alp; Önder, Tuğba Bağcı; Gönen, Mehmet; PhD Student; Faculty Member; Department of Industrial Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; N/A; N/A; N/A; 184359; 237468
    High mortality rates of glioblastoma (GBM) patients are partly attributed to the invasive behavior of tumor cells that exhibit extensive infiltration into adjacent brain tissue, leading to rapid, inevitable, and therapy-resistant recurrence. In this study, we analyzed transcriptome of motile (dispersive) and non-motile (core) GBM cells using an in vitro spheroid dispersal model and identified SERPINE1 as a modulator of GBM cell dispersal. Genetic or pharmacological inhibition of SERPINE1 reduced spheroid dispersal and cell adhesion by regulating cell-substrate adhesion. We examined TGFβ as a potential upstream regulator of SERPINE1 expression. We also assessed the significance of SERPINE1 in GBM growth and invasion using TCGA glioma datasets and a patient-derived orthotopic GBM model. SERPINE1 expression was associated with poor prognosis and mesenchymal GBM in patients. SERPINE1 knock-down in primary GBM cells suppressed tumor growth and invasiveness in the brain. Together, our results indicate that SERPINE1 is a key player in GBM dispersal and provide insights for future anti-invasive therapy design.
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    PublicationOpen Access
    Drug repositioning screen on a new primary cell line identifies potent therapeutics for glioblastoma
    (Frontiers, 2020) Şenbabaoğlu, Filiz; Cingöz, Ahmet; Şeker-Polat, Fidan; Önder, Tuğba Bağcı; Aksu, Ali Cenk; Börklü Yücel, Esra; Solaroğlu, İhsan; PhD Student; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; Koç University Hospital; N/A; N/A; N/A; 184359; N/A; N/A; 102059
    Glioblastoma is a malignant brain cancer with limited treatment options and high mortality rate. While established glioblastoma cell line models provide valuable information, they ultimately lose most primary characteristics of tumors under long-term serum culture conditions. Therefore, established cell lines do not necessarily recapitulate genetic and morphological characteristics of real tumors. In this study, in line with the growing interest in using primary cell line models derived from patient tissue, we generated a primary glioblastoma cell line, KUGBM8 and characterized its genetic alterations, long term growth ability, tumor formation capacity and its response to Temozolomide, the front-line chemotherapy utilized clinically. In addition, we performed a drug repurposing screen on the KUGBM8 cell line to identify FDA-approved agents that can be incorporated into glioblastoma treatment regimen and identified Topotecan as a lead drug among 1,200 drugs. We showed Topotecan can induce cell death in KUGBM8 and other primary cell lines and cooperate with Temozolomide in low dosage combinations. Together, our study provides a new primary cell line model that can be suitable for both in vitro and in vivo studies and suggests that Topotecan can offer promise as a therapeutic approach for glioblastoma.
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    The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma
    (Nature Publishing Group (NPG), 2019) Gezen, Melike; Tolay, Nazife; Erman, Batu; Dunford, James; Oppermann, Udo; N/A; Department of Industrial Engineering; Department of Molecular Biology and Genetics; N/A; Uyulur, Fırat; Gönen, Mehmet; Önder, Tuğba Bağcı; Özyerli, Ezgi; Sur, İlknur Erdem; Şeker-Polat, Fidan; Cingöz, Ahmet; Kayabölen, Alişan; Kahya, Zeynep; Faculty Member; Department of Industrial Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; Graduate School of Health Sciences; N/A; 237468; 184359; N/A; N/A; N/A; N/A; N/A; N/A
    Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.