Eli Bar - Academia.edu (original) (raw)

Papers by Eli Bar

Research paper thumbnail of DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts

Research paper thumbnail of Spatial enrichment of cellular states in glioblastoma

Acta Neuropathologica, 2020

Research paper thumbnail of Abstract 1038: ZEB1 plays a pivotal role in hypoxia-mediated increase of in vitro invasion of glioblastoma-derived cell cultures and represents a novel neural stem cell marker in early development

Cancer Research, 2014

Objective Hypoxia is thought to induce migration in many neoplasms, often by promoting epithelial... more Objective Hypoxia is thought to induce migration in many neoplasms, often by promoting epithelial-to-mesenchymal transition (EMT), but the mechanisms by which it affects brain tumor invasion is less well understood. In particular, little is known about the possible role of EMT-associated factors in hypoxia-mediated induction of migratory phenotype in gliomas. Methods Migration and invasion of GBM-derived cell lines (n=3) cultivated as spheres in serum-free media under atmospheric oxygen (21% O2) and hypoxia (1% O2) were assessed in Boyden Chamber-based in vitro assays. Digoxin was used to inhibit the HIF-1-mediated hypoxic response. The importance of the EMT-factor ZEB1 in our model was investigated by inhibiting its expression using sh-RNA delivered by lentivirus. Results Hypoxia led to a significant increase of in vitro invasion in all three neurosphere lines tested (GBM1 up to 6fold, 622 up to 3fold and over 10fold for 821; p=0.001). This was accompanied by induction of EMT effec...

Research paper thumbnail of Abstract 3954: SAT1 (Spermidine/spermine-N1-acetyltrasferase 1) promotes radiation resistance in glioblastoma multiforme

Cancer Research, 2014

Glioblastoma multiforme (GBM), is the most common and severe form of brain cancer. The median sur... more Glioblastoma multiforme (GBM), is the most common and severe form of brain cancer. The median survival time is approximately 14 months due to poor responses to surgery, radiation and chemotherapy. GBM cells have been shown to exhibit high resistance to radiation. In order to understand the mechanisms involved in radioresistance, we conducted a genetic screen using a shRNA library on GBM cell lines to identify genes whose inhibition would sensitize cells to radiation. The results were cross-referred with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors, and are associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors and its high expression correlates with poor outcomes. The objective of this study is to explore the role of SAT1 in radioresistance with the purpose of targeting SAT1 as a means to sensitize tumors. The knockdown of SAT1 using, shRNA and siRNA approaches, in multiple cell lines and neurosphere lines results in sensitization of GBM cells to radiation in colony formation assays. This was seen specifically in G2/M and S phases, leading to the hypothesis that SAT1 plays a role in homologous recombination (HR). By measuring HR in the DR-GFP reporter system, we confirmed that SAT1 promotes HR, since depletion of SAT1 results in decrease in HR. To test whether SAT1 depletion sensitizes cells to S-phase poisons, SAT1 knockdown GBM cells were then exposed to camptothecin, and were found to be sensitized. To explore the mechanisms of interaction of SAT1 with the DNA damage pathway, chromatin immunoprecipitation (ChIP) was performed under the theory that polyamine-DNA interactions may be altered during DNA repair. The results show that polyamines are decreased in the chromatin of the HR site following induction of double-strand breaks. Interestingly, western blot analyses show that SAT1 knockdown decreases the levels of acetylated histone 3 (H3) proteins, suggesting a new role of SAT1 in chromatin remodeling. Overall the results suggest that SAT1 is involved in radioresistance in GBM through regulation of HR and alterations in chromatin remodeling at sites of damage. Our findings suggest that the biological significance of SAT1 expression in GBM lies in its contribution to cell radioresistance and SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies. Citation Format: Adina Brett-Morris, Scott M. Welford, Eli Bar, Raffaella Spina, Bradley Wright, Junran Zhang, Jun Lu, Yuji Seo. SAT1 (Spermidine/spermine-N1-acetyltrasferase 1) promotes radiation resistance in glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3954. doi:10.1158/1538-7445.AM2014-3954

Research paper thumbnail of Abstract 3040: Forced astroglial differentiation depletes glioblastoma stem cells

Cancer Research, 2014

Glioblastoma are among the least curable cancers in man, at least in part because of stem-like ce... more Glioblastoma are among the least curable cancers in man, at least in part because of stem-like cellular subpopulations (herein referred to as glioma stem cells, GSC) refractory to current therapies. The cancer stem cell hypothesis suggests that tumor cells are organized in a pyramidal unidirectional differentiation cascade with GSC at the top and functionally defined by the ability to self-renew and initiate tumors identical to the original tumors from which they are derived. GSCs are maintained by both cell intrinsic and microenvironmental factors and conditions. In this study we focused on identifying potential small molecules which may target tumor heterogeneity by promoting differentiation of GSC into less aggressive, more differentiated subpopulations. To this end, we have developed reporter models for astroglial and neuronal differentiation in HSR-GBM1, HSR040622 and HSR040821 tumor-derived, GSC-enriched, neurospheres lines, using lineage-specific reporter constructs. We emplo...

Research paper thumbnail of Abstract 2930: Silencing MCT4 inhibits GBM growth, HIF response, and CD133-positive fraction in a lactate-independent fashion

Cancer Research, 2013

Glioblastomas (GBM) contain a hypoxic core surrounded by proliferative cells. Our group and other... more Glioblastomas (GBM) contain a hypoxic core surrounded by proliferative cells. Our group and others have shown that GBM stem cells favor a hypoxic microenvironment, and it is believed that many reside in the tumor core. Conventional therapies target the tumor bulk, but may spare stem cells in the hypoxic niche. To patch this therapeutic loophole, we sought to target the GBM stem cell microenvironment by identifying genes that are important for survival in hypoxia. We identified monocarboxylate transporter 4 (MCT4) as one of the most upregulated genes in our GBM neurosphere lines in response to hypoxia. Clinically, GBM patients with a two-fold or more upregulation of MCT4 have a significantly shorter survival (p = 0.036) than patients with intermediate expression. Consistent with this data, MCT4 upregulation correlated with the aggressive mesenchymal subset of GBM (p<0.0001). Using immunohistochemical analysis, we also found that MCT4 protein levels are increased in high-grade as c...

Research paper thumbnail of Abstract 3776: Hypoxia-inducible factor 1α (HIF1α) has a prometastatic effect in uveal melanoma

Cancer Research, 2013

Melanomas arising from the uveal tract of the eye represent the most frequent primary intraocular... more Melanomas arising from the uveal tract of the eye represent the most frequent primary intraocular malignancy in adults and are the second most common type of melanoma. Uveal melanomas are prone to disseminate hematogenously to the liver, and have an overall survival rate of approximately 50%. Hypoxia-inducible factor 1α (HIF1α), a master transcriptional regulator of the hypoxic response, is strongly associated with aggressive uveal melanomas. Elevated expression of one of the HIF target gene lysyl oxidase (LOX) has been found at the invasive front of primary tumors, and is associated with shorter metastasis-free survival. Here we investigated the mechanism responsible for the prometastatic effect of HIF1α in uveal melanoma. Western blot examination of HIF1α and HIF2α proteins in uveal melanoma cell lines grown in normoxia (21% pO2) and in hypoxia (1% pO2) revealed HIF2α to be low. In contrast, HIF1α protein was relatively abundant in the OCM1, OCM3, OMM1, Mel290 and 92.1 uveal melan...

Research paper thumbnail of Nestin is Required for Glioma Cell Migration

Research paper thumbnail of Hypoxia Increases CD133-Percentage And Clonogenicity In Brain Tumor Neurospheres

Research paper thumbnail of Using the Natural Remedies Zeng Sheng Ping and Curcumin to Treat Medulloblastoma and Glioblastoma

Research paper thumbnail of Using nanocurcumin to treat medulloblastoma and glioblastoma

Research paper thumbnail of Braf Induces Cellular Transformation and Senescence in Human Neural Stem Cells: A Model of Pilocytic Astrocytoma

Research paper thumbnail of Expression of oncogene-induced senescence markers in pilocytic astrocytomaIs associated with younger age and longer survival

Research paper thumbnail of BRAF activation induces cellular transformation and senescence and down-regulates SOX2 in human neural stem cells: a model of pilocytic astrocytoma

Research paper thumbnail of Braf Activation Induces Cellular Transformation and Senescence and Downregulates SOX2 and BMI1 in Human Neural Stem Cells: A Model of Pilocytic Astrocytoma

Research paper thumbnail of Expression of Notch Pathway Members in Pilocytic Astrocytoma

Research paper thumbnail of The potential role of lateral inhibition in the maintenance of glioblastoma cancer stem cells

Research paper thumbnail of Inhibition of Monocarboxylate Transporter 4 (MCT4) targets stem-like cells in glioblastoma

Research paper thumbnail of Identification of Biologically Relevant Targets in Pilocytic Astrocytoma by MicroRNA Profiling

Research paper thumbnail of MicroRNA PROFILING OF PEDIATRIC PILOCYTIC ASTROCYTOMA REVEALS BIOLOGICALLY RELEVANT TARGETS

Research paper thumbnail of DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts

Research paper thumbnail of Spatial enrichment of cellular states in glioblastoma

Acta Neuropathologica, 2020

Research paper thumbnail of Abstract 1038: ZEB1 plays a pivotal role in hypoxia-mediated increase of in vitro invasion of glioblastoma-derived cell cultures and represents a novel neural stem cell marker in early development

Cancer Research, 2014

Objective Hypoxia is thought to induce migration in many neoplasms, often by promoting epithelial... more Objective Hypoxia is thought to induce migration in many neoplasms, often by promoting epithelial-to-mesenchymal transition (EMT), but the mechanisms by which it affects brain tumor invasion is less well understood. In particular, little is known about the possible role of EMT-associated factors in hypoxia-mediated induction of migratory phenotype in gliomas. Methods Migration and invasion of GBM-derived cell lines (n=3) cultivated as spheres in serum-free media under atmospheric oxygen (21% O2) and hypoxia (1% O2) were assessed in Boyden Chamber-based in vitro assays. Digoxin was used to inhibit the HIF-1-mediated hypoxic response. The importance of the EMT-factor ZEB1 in our model was investigated by inhibiting its expression using sh-RNA delivered by lentivirus. Results Hypoxia led to a significant increase of in vitro invasion in all three neurosphere lines tested (GBM1 up to 6fold, 622 up to 3fold and over 10fold for 821; p=0.001). This was accompanied by induction of EMT effec...

Research paper thumbnail of Abstract 3954: SAT1 (Spermidine/spermine-N1-acetyltrasferase 1) promotes radiation resistance in glioblastoma multiforme

Cancer Research, 2014

Glioblastoma multiforme (GBM), is the most common and severe form of brain cancer. The median sur... more Glioblastoma multiforme (GBM), is the most common and severe form of brain cancer. The median survival time is approximately 14 months due to poor responses to surgery, radiation and chemotherapy. GBM cells have been shown to exhibit high resistance to radiation. In order to understand the mechanisms involved in radioresistance, we conducted a genetic screen using a shRNA library on GBM cell lines to identify genes whose inhibition would sensitize cells to radiation. The results were cross-referred with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors, and are associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors and its high expression correlates with poor outcomes. The objective of this study is to explore the role of SAT1 in radioresistance with the purpose of targeting SAT1 as a means to sensitize tumors. The knockdown of SAT1 using, shRNA and siRNA approaches, in multiple cell lines and neurosphere lines results in sensitization of GBM cells to radiation in colony formation assays. This was seen specifically in G2/M and S phases, leading to the hypothesis that SAT1 plays a role in homologous recombination (HR). By measuring HR in the DR-GFP reporter system, we confirmed that SAT1 promotes HR, since depletion of SAT1 results in decrease in HR. To test whether SAT1 depletion sensitizes cells to S-phase poisons, SAT1 knockdown GBM cells were then exposed to camptothecin, and were found to be sensitized. To explore the mechanisms of interaction of SAT1 with the DNA damage pathway, chromatin immunoprecipitation (ChIP) was performed under the theory that polyamine-DNA interactions may be altered during DNA repair. The results show that polyamines are decreased in the chromatin of the HR site following induction of double-strand breaks. Interestingly, western blot analyses show that SAT1 knockdown decreases the levels of acetylated histone 3 (H3) proteins, suggesting a new role of SAT1 in chromatin remodeling. Overall the results suggest that SAT1 is involved in radioresistance in GBM through regulation of HR and alterations in chromatin remodeling at sites of damage. Our findings suggest that the biological significance of SAT1 expression in GBM lies in its contribution to cell radioresistance and SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies. Citation Format: Adina Brett-Morris, Scott M. Welford, Eli Bar, Raffaella Spina, Bradley Wright, Junran Zhang, Jun Lu, Yuji Seo. SAT1 (Spermidine/spermine-N1-acetyltrasferase 1) promotes radiation resistance in glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3954. doi:10.1158/1538-7445.AM2014-3954

Research paper thumbnail of Abstract 3040: Forced astroglial differentiation depletes glioblastoma stem cells

Cancer Research, 2014

Glioblastoma are among the least curable cancers in man, at least in part because of stem-like ce... more Glioblastoma are among the least curable cancers in man, at least in part because of stem-like cellular subpopulations (herein referred to as glioma stem cells, GSC) refractory to current therapies. The cancer stem cell hypothesis suggests that tumor cells are organized in a pyramidal unidirectional differentiation cascade with GSC at the top and functionally defined by the ability to self-renew and initiate tumors identical to the original tumors from which they are derived. GSCs are maintained by both cell intrinsic and microenvironmental factors and conditions. In this study we focused on identifying potential small molecules which may target tumor heterogeneity by promoting differentiation of GSC into less aggressive, more differentiated subpopulations. To this end, we have developed reporter models for astroglial and neuronal differentiation in HSR-GBM1, HSR040622 and HSR040821 tumor-derived, GSC-enriched, neurospheres lines, using lineage-specific reporter constructs. We emplo...

Research paper thumbnail of Abstract 2930: Silencing MCT4 inhibits GBM growth, HIF response, and CD133-positive fraction in a lactate-independent fashion

Cancer Research, 2013

Glioblastomas (GBM) contain a hypoxic core surrounded by proliferative cells. Our group and other... more Glioblastomas (GBM) contain a hypoxic core surrounded by proliferative cells. Our group and others have shown that GBM stem cells favor a hypoxic microenvironment, and it is believed that many reside in the tumor core. Conventional therapies target the tumor bulk, but may spare stem cells in the hypoxic niche. To patch this therapeutic loophole, we sought to target the GBM stem cell microenvironment by identifying genes that are important for survival in hypoxia. We identified monocarboxylate transporter 4 (MCT4) as one of the most upregulated genes in our GBM neurosphere lines in response to hypoxia. Clinically, GBM patients with a two-fold or more upregulation of MCT4 have a significantly shorter survival (p = 0.036) than patients with intermediate expression. Consistent with this data, MCT4 upregulation correlated with the aggressive mesenchymal subset of GBM (p<0.0001). Using immunohistochemical analysis, we also found that MCT4 protein levels are increased in high-grade as c...

Research paper thumbnail of Abstract 3776: Hypoxia-inducible factor 1α (HIF1α) has a prometastatic effect in uveal melanoma

Cancer Research, 2013

Melanomas arising from the uveal tract of the eye represent the most frequent primary intraocular... more Melanomas arising from the uveal tract of the eye represent the most frequent primary intraocular malignancy in adults and are the second most common type of melanoma. Uveal melanomas are prone to disseminate hematogenously to the liver, and have an overall survival rate of approximately 50%. Hypoxia-inducible factor 1α (HIF1α), a master transcriptional regulator of the hypoxic response, is strongly associated with aggressive uveal melanomas. Elevated expression of one of the HIF target gene lysyl oxidase (LOX) has been found at the invasive front of primary tumors, and is associated with shorter metastasis-free survival. Here we investigated the mechanism responsible for the prometastatic effect of HIF1α in uveal melanoma. Western blot examination of HIF1α and HIF2α proteins in uveal melanoma cell lines grown in normoxia (21% pO2) and in hypoxia (1% pO2) revealed HIF2α to be low. In contrast, HIF1α protein was relatively abundant in the OCM1, OCM3, OMM1, Mel290 and 92.1 uveal melan...

Research paper thumbnail of Nestin is Required for Glioma Cell Migration

Research paper thumbnail of Hypoxia Increases CD133-Percentage And Clonogenicity In Brain Tumor Neurospheres

Research paper thumbnail of Using the Natural Remedies Zeng Sheng Ping and Curcumin to Treat Medulloblastoma and Glioblastoma

Research paper thumbnail of Using nanocurcumin to treat medulloblastoma and glioblastoma

Research paper thumbnail of Braf Induces Cellular Transformation and Senescence in Human Neural Stem Cells: A Model of Pilocytic Astrocytoma

Research paper thumbnail of Expression of oncogene-induced senescence markers in pilocytic astrocytomaIs associated with younger age and longer survival

Research paper thumbnail of BRAF activation induces cellular transformation and senescence and down-regulates SOX2 in human neural stem cells: a model of pilocytic astrocytoma

Research paper thumbnail of Braf Activation Induces Cellular Transformation and Senescence and Downregulates SOX2 and BMI1 in Human Neural Stem Cells: A Model of Pilocytic Astrocytoma

Research paper thumbnail of Expression of Notch Pathway Members in Pilocytic Astrocytoma

Research paper thumbnail of The potential role of lateral inhibition in the maintenance of glioblastoma cancer stem cells

Research paper thumbnail of Inhibition of Monocarboxylate Transporter 4 (MCT4) targets stem-like cells in glioblastoma

Research paper thumbnail of Identification of Biologically Relevant Targets in Pilocytic Astrocytoma by MicroRNA Profiling

Research paper thumbnail of MicroRNA PROFILING OF PEDIATRIC PILOCYTIC ASTROCYTOMA REVEALS BIOLOGICALLY RELEVANT TARGETS