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Richard Sposto - One of the best experts on this subject based on the ideXlab platform.
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anti cd105 antibody eliminates tumor microenvironment cells and enhances anti gd2 antibody immunotherapy of Neuroblastoma with activated natural killer cells
Clinical Cancer Research, 2019Co-Authors: Michael A Sheard, Jemily Malvar, Esteban G Fernandez, Yves A Declerck, Laurence Blavier, Hiroyuki Shimada, Charles P Theuer, Richard SpostoAbstract:Purpose: We determined whether elimination of CD105+ cells in the tumor microenvironment (TME) with anti-CD105 antibodies enhanced anti-disialoganglioside (GD2) antibody dinutuximab therapy of Neuroblastoma when combined with activated natural killer (aNK) cells. Experimental Design: The effect of MSCs and monocytes on antibody-dependent cellular cytotoxicity (ADCC) mediated by dinutuximab with aNK cells against Neuroblastoma cells was determined in vitro. ADCC with anti-CD105 mAb TRC105 and aNK cells against MSCs, monocytes, and endothelial cells, which express CD105, was evaluated. Anti-Neuroblastoma activity in immunodeficient NSG mice of dinutuximab with aNK cells without or with anti-CD105 mAbs was determined using Neuroblastoma cell lines and a patient-derived xenograft. Results: ADCC mediated by dinutuximab with aNK cells against Neuroblastoma cells in vitro was suppressed by addition of MSCs and monocytes, and dinutuximab with aNK cells was less effective against Neuroblastomas formed with coinjected MSCs and monocytes in NSG mice than against those formed by tumor cells alone. Anti-CD105 antibody TRC105 with aNK cells mediated ADCC against MSCs, monocytes, and endothelial cells. Neuroblastomas formed in NSG mice by two Neuroblastoma cell lines or a patient-derived xenograft coinjected with MSCs and monocytes were most effectively treated with dinutuximab and aNK cells when anti-human (TRC105) and anti-mouse (M1043) CD105 antibodies were added, which depleted human MSCs and murine endothelial cells and macrophages from the TME. Conclusions: Immunotherapy of Neuroblastoma with anti-GD2 antibody dinutuximab and aNK cells is suppressed by CD105+ cells in the TME, but suppression is overcome by adding anti-CD105 antibodies to eliminate CD105+ cells.
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tgfβr1 blockade with galunisertib ly2157299 enhances anti Neuroblastoma activity of the anti gd2 antibody dinutuximab ch14 18 with natural killer cells
Clinical Cancer Research, 2017Co-Authors: Jeremy R Jackson, Jianping Sun, Zesheng Wan, Jemily Malvar, Michael A Sheard, Larry Wang, Hung C Tran, Richard SpostoAbstract:Purpose: Immunotherapy of high-risk Neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against Neuroblastoma. Experimental Design: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary Neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by Neuroblastoma patient blood and bone marrow plasmas in Neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-Neuroblastoma activity in NSG mice was determined. Results: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in Neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human Neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors, TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against NB cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two Neuroblastoma cell lines or a patient-derived xenograft. Conclusions: Galunisertib suppresses activation of SMAD2 in Neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against Neuroblastoma tumors.
Peter F Ambros - One of the best experts on this subject based on the ideXlab platform.
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demethylation of repetitive dna sequences in Neuroblastoma
Genes Chromosomes and Cancer, 1996Co-Authors: Didier Thoraval, Jun Ichi Asakawa, Katharina Wimmer, Rork Kuick, Barbara J Lamb, Bruce Richardson, Peter F Ambros, Thomas W Glover, Samir M HanashAbstract:Altered genomic methylcytosine content has been described for a number of tumor types, including Neuroblastoma. However, it remains to be determined for different tumor types whether specific loci or chromosomal regions are affected by a methylation change or whether the change is random. We have implemented a computer-based approach for the analysis of two-dimensional separations of human genomic restriction fragments. Through the use of methylation-sensitive restriction enzymes, methylation differences in genomic DNA between tumor and normal tissues can be detected. We report the cloning and sequencing of two fragments detectable in two-dimensional separations of genomic DNA of Neuroblastomas. These fragments were found to be a part of repetitive units that exhibited demethylation in Neuroblastoma relative to other tumor types. Our finding of a distinct pattern of methylation of repetitive units in Neuroblastoma suggests that altered methylation at certain loci may contribute to the biology of this tumor.
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role of ploidy chromosome 1p and schwann cells in the maturation of Neuroblastoma
The New England Journal of Medicine, 1996Co-Authors: I M Ambros, Andrea Zellner, Borghild Roald, Gabriele Amann, Ruth Ladenstein, Dieter Printz, H Gadner, Peter F AmbrosAbstract:BACKGROUND: Neuroblastoma is a heterogeneous disease, with manifestations ranging from spontaneous regression to lethal spread. Sometimes the tumor spontaneously differentiates toward a benign ganglioneuroma (maturing Neuroblastoma). The prognosis is frequently related to ploidy, deletions in the short arm of chromosome 1, and amplifications of the N-myc oncogene. Maturing Neuroblastomas consist of both neuronal cells and Schwann cells. We investigated the genetic composition of both cell types in maturing Neuroblastomas, to determine the relation between genetic abnormalities and maturation. METHODS: We studied 20 maturing and mature Neuroblastomas by in situ hybridization to count the chromosomes and evaluate possible deletions in the short arm of chromosome 1 in neuronal and Schwann cells. The DNA content of the cells was measured by flow cytometry. RESULTS: Neuroblastic and ganglionic cells showed aberrations in the number of chromosomes. In situ hybridization and flow cytometry demonstrated near-trip-loidy in 18 of 19 tumors and pentaploidy in the remaining tumor. The Schwann cells in all 20 Neuroblastomas contained normal numbers of chromosomes. In 18 tumors studied, there were no chromosome 1 deletions in either type of cell. CONCLUSIONS: The Schwann cells in maturing Neuroblastomas differ genetically from the neuronal cells. The normal number of chromosomes in Schwann cells and the abnormal number in neuroblastic ganglionic cells suggests that Schwann cells are a reactive population of normal cells that invade the Neuroblastoma. Near-trip-loidy of Neuroblastoma cells and intact chromosome 1 are presumably genetic prerequisites for spontaneous organoid maturation, because we found no diploidy or chromosome 1 depletions in the neuronal cells of spontaneously maturing Neuroblastomas.
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role of ploidy chromosome 1p and schwann cells in the maturation of Neuroblastoma
The New England Journal of Medicine, 1996Co-Authors: I M Ambros, Andrea Zellner, Borghild Roald, Gabriele Amann, Ruth Ladenstein, Dieter Printz, H Gadner, Peter F AmbrosAbstract:BackgroundNeuroblastoma is a heterogeneous disease, with manifestations ranging from spontaneous regression to lethal spread. Sometimes the tumor spontaneously differentiates toward a benign ganglioneuroma (maturing Neuroblastoma). The prognosis is frequently related to ploidy, deletions in the short arm of chromosome 1, and amplifications of the N-myc oncogene. Maturing Neuroblastomas consist of both neuronal cells and Schwann cells. We investigated the genetic composition of both cell types in maturing Neuroblastomas, to determine the relation between genetic abnormalities and maturation. MethodsWe studied 20 maturing and mature Neuroblastomas by in situ hybridization to count the chromosomes and evaluate possible deletions in the short arm of chromosome 1 in neuronal and Schwann cells. The DNA content of the cells was measured by flow cytometry. ResultsNeuroblastic and ganglionic cells showed aberrations in the number of chromosomes. In situ hybridization and flow cytometry demonstrated near-triploidy ...
Mark W Zimmerman - One of the best experts on this subject based on the ideXlab platform.
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retinoic acid rewires the adrenergic core regulatory circuitry of childhood Neuroblastoma
bioRxiv, 2021Co-Authors: Mark W Zimmerman, Ting Tao, Adam D Durbin, Felix Oppel, Alla Berezovskaya, Hui Shi, Yu LiuAbstract:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For Neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here we show that when MYCN-amplified Neuroblastomas cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1 and SOX4 expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in downregulation of MYCN expression, while establishing a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids in high-risk Neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of amplification of this gene.
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retinoic acid rewires the adrenergic core regulatory circuitry of Neuroblastoma but can be subverted by enhancer hijacking of myc or mycn
bioRxiv, 2020Co-Authors: Mark W Zimmerman, Adam D Durbin, Shijie He, Felix Oppel, Zhongchi Li, Alla Berezovskaya, Juanwen Zhang, Richard A Young, Brian J Abraham, A T LookAbstract:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For Neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary Neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified Neuroblastomas cells are treated with all-trans retinoic acid (ATRA), histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1, HIC1 and SOX4 expression. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, resulting in downregulation of MYCN expression, while upregulating a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk Neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.
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myc drives a subset of high risk pediatric Neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
Cancer Discovery, 2017Co-Authors: Mark W Zimmerman, Xiaoling Zhang, Adam D Durbin, Brian J Abraham, Shuning He, John Easton, Ying Shao, Beisi Xu, Zhaodong Li, Nina WeichertleaheyAbstract:The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric Neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk Neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform Neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood Neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric Neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of Neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253
Nina Weichertleahey - One of the best experts on this subject based on the ideXlab platform.
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cross cohort analysis identifies a tead4 mycn positive feedback loop as the core regulatory element of high risk Neuroblastoma
Cancer Discovery, 2018Co-Authors: Presha Rajbhandari, Daniel Martinez, Gonzalo Lopez, Claudia Capdevila, Eatrice Salvatori, Ruth Rodriguezbarrueco, Mark Yarmarkovich, Nina WeichertleaheyAbstract:High-risk Neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk Neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) Neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated Neuroblastomas.Significance: Despite progress in understanding of Neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining Neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp Neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
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myc drives a subset of high risk pediatric Neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
Cancer Discovery, 2017Co-Authors: Mark W Zimmerman, Xiaoling Zhang, Adam D Durbin, Brian J Abraham, Shuning He, John Easton, Ying Shao, Beisi Xu, Zhaodong Li, Nina WeichertleaheyAbstract:The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric Neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk Neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform Neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood Neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric Neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of Neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253
Adam D Durbin - One of the best experts on this subject based on the ideXlab platform.
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retinoic acid rewires the adrenergic core regulatory circuitry of childhood Neuroblastoma
bioRxiv, 2021Co-Authors: Mark W Zimmerman, Ting Tao, Adam D Durbin, Felix Oppel, Alla Berezovskaya, Hui Shi, Yu LiuAbstract:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For Neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here we show that when MYCN-amplified Neuroblastomas cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1 and SOX4 expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in downregulation of MYCN expression, while establishing a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids in high-risk Neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of amplification of this gene.
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retinoic acid rewires the adrenergic core regulatory circuitry of Neuroblastoma but can be subverted by enhancer hijacking of myc or mycn
bioRxiv, 2020Co-Authors: Mark W Zimmerman, Adam D Durbin, Shijie He, Felix Oppel, Zhongchi Li, Alla Berezovskaya, Juanwen Zhang, Richard A Young, Brian J Abraham, A T LookAbstract:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For Neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary Neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified Neuroblastomas cells are treated with all-trans retinoic acid (ATRA), histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1, HIC1 and SOX4 expression. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, resulting in downregulation of MYCN expression, while upregulating a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk Neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.
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myc drives a subset of high risk pediatric Neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
Cancer Discovery, 2017Co-Authors: Mark W Zimmerman, Xiaoling Zhang, Adam D Durbin, Brian J Abraham, Shuning He, John Easton, Ying Shao, Beisi Xu, Zhaodong Li, Nina WeichertleaheyAbstract:The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric Neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk Neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform Neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood Neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric Neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of Neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253
