10 results on '"Jonathan M Goeldner"'
Search Results
2. Inhibition of metabotropic glutamate receptor III facilitates sensitization to alkylating chemotherapeutics in glioblastoma
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Julian P. Maier, Vidhya M. Ravi, Jan Kueckelhaus, Simon P. Behringer, Niklas Garrelfs, Paulina Will, Na Sun, Jasmin von Ehr, Jonathan M. Goeldner, Dietmar Pfeifer, Marie Follo, Luciana Hannibal, Axel Karl Walch, Ulrich G. Hofmann, Jürgen Beck, Dieter Henrik Heiland, Oliver Schnell, and Kevin Joseph
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Cytology ,QH573-671 - Abstract
Abstract Glioblastoma (GBM), the most malignant tumor of the central nervous system, is marked by its dynamic response to microenvironmental niches. In particular, this cellular plasticity contributes to the development of an immediate resistance during tumor treatment. Novel insights into the developmental trajectory exhibited by GBM show a strong capability to respond to its microenvironment by clonal selection of specific phenotypes. Using the same mechanisms, malignant GBM do develop intrinsic mechanisms to resist chemotherapeutic treatments. This resistance was reported to be sustained by the paracrine and autocrine glutamate signaling via ionotropic and metabotropic receptors. However, the extent to which glutamatergic signaling modulates the chemoresistance and transcriptional profile of the GBM remains unexplored. In this study we aimed to map the manifold effects of glutamate signaling in GBM as the basis to further discover the regulatory role and interactions of specific receptors, within the GBM microenvironment. Our work provides insights into glutamate release dynamics, representing its importance for GBM growth, viability, and migration. Based on newly published multi-omic datasets, we explored the and characterized the functions of different ionotropic and metabotropic glutamate receptors, of which the metabotropic receptor 3 (GRM3) is highlighted through its modulatory role in maintaining the ability of GBM cells to evade standard alkylating chemotherapeutics. We addressed the clinical relevance of GRM3 receptor expression in GBM and provide a proof of concept where we manipulate intrinsic mechanisms of chemoresistance, driving GBM towards chemo-sensitization through GRM3 receptor inhibition. Finally, we validated our findings in our novel human organotypic section-based tumor model, where GBM growth and proliferation was significantly reduced when GRM3 inhibition was combined with temozolomide application. Our findings present a new picture of how glutamate signaling via mGluR3 interacts with the phenotypical GBM transcriptional programs in light of recently published GBM cell-state discoveries.
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- 2021
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3. Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma
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Simon P Behringer, Vidhya M Ravi, Oliver Schnell, Jasim Kada Benotmane, Henrike Salié, Marie Follo, Daniel Delev, Marius Schwabenland, Ulrich G. Hofmann, Melanie Boerries, Jonathan M Goeldner, Mohammed Khiat, Christian Fung, Manching Ku, Axel Walch, Jürgen Beck, Dieter Henrik Heiland, Ugne Kuliesiute, Florian Scherer, Ulrich Schüller, Paulina Will, Lea Vollmer, Na Sun, Pamela Franco, Roman Sankowski, Jasmin von Ehr, Kevin Joseph, Marco Prinz, Katrin Lamszus, Franz Ricklefs, Junyi Zhang, Jan Kueckelhaus, Saskia Killmer, Nicolas Neidert, and Bertram Bengsch
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Cancer Research ,Spatial segregation ,Tissue mimicking phantom ,Brain Neoplasms ,Spatially resolved ,genomic instability ,glioblastoma heterogeneity ,imaging mass cytometry ,MALDI ,microenvironment ,multiomics ,spatially resolved transcriptomics ,tumor ecosystem ,Ethics committee ,Computational biology ,Biology ,medicine.disease ,Environmental stress ,Oncology ,medicine ,Multi omics ,Humans ,Metabolomics ,Christian ministry ,Glioblastoma - Abstract
Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of the dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas in-depth by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering regional shared transcriptional programs across patients, we infer that glioblastomas are organized by spatial segregation of lineage states and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Integration of metabolic imaging and image mass cytometry uncovered locoregional tumor-host interdependence resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments. Funding: DHH is funded by the Else Kroner-Fresenius Foundation. The work is part of the MEPHISTO project (PI: DHH and DD), funded by BMBF (iGerman Ministry of Education and Research) (project number: 031L0260B). The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supports the work of AW (project number: SFB 824 C04). VR, KJ and UGH funded by BMBF (Bundes Ministerium fur Bildung und Forschung) (project number: FMT 13GW0230A), US was supported by the Fordergemeinschaft Kinderkrebszentrum Hamburg. We thank Dietmar Pfeifer for here helpful advice. We thank Biorender.com. We thank Stella Maria Carro for her support and the provision of her laboratory facilities and equipment. Declaration of Interest: No potential conflicts of interest were disclosed by the authors. Ethical Approval: The local ethics committee of the University of Freiburg approved the data evaluation, imaging procedures and experimental design (protocol 100020/09 and 472/15_160880).
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- 2022
4. Cyclooxygenase (COX) Inhibition by Acetyl Salicylic Acid (ASA) Enhances Antitumor Effects of Nitric Oxide in Glioblastoma In Vitro
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Jessica Guenzle, Nicklas W C Garrelfs, Astrid Weyerbrock, and Jonathan M Goeldner
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0301 basic medicine ,Time Factors ,Cell Survival ,Angiogenesis ,Neuroscience (miscellaneous) ,Brain tumor ,Antineoplastic Agents ,Nitric Oxide ,Piperazines ,Nitric oxide ,Necrosis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Glioma ,medicine ,Humans ,Cyclooxygenase Inhibitors ,Nitric Oxide Donors ,Aspirin ,biology ,Drug Synergism ,Glutathione ,medicine.disease ,Up-Regulation ,030104 developmental biology ,Neurology ,chemistry ,Apoptosis ,biology.protein ,Cancer research ,Cyclooxygenase ,Glioblastoma ,Azo Compounds ,030217 neurology & neurosurgery ,Salicylic acid - Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a high recurrence rate and a median survival of about 16 months even with multimodal therapy. Novel experimental strategies against malignant gliomas include cyclooxygenase (COX) inhibition and nitric oxide (NO)-based therapies. Therapeutic doses of NO can be delivered to tumor cells by NO donors such as JS-K (O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) which releases NO upon enzymatic activation by glutathione S-transferase. COX-2 is frequently overexpressed in tumors and increases tumor invasiveness and angiogenesis. In this study, we show that pretreatment with acetyl salicylic acid (ASA) enhanced the cytotoxic antitumor effect of NO in vitro. Combination of low doses of JS-K and ASA revealed a dose-dependent synergistic increase of necrotic cell death under circumvention of classical apoptosis and alteration of the metabolic calcium level. These findings provide an opportunity to improve currently used therapeutic strategies in the treatment of gliomas with a well-established remedy.
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- 2019
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5. Crosstalk between lymphoid and myeloid cells orchestrates glioblastoma immunity through Interleukin 10 signaling
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Florian Scherer, Jonathan M Goeldner, Dieter Henrik Heiland, Julius M Kernbach, Tobias Weiss, Marco Prinz, Kevin Joseph, Pamela Franco, Roman Sankowski, Jan Kückelhaus, Christine Dierks, Maria Stella Carro, Julian P Maier, Nicolas Neidert, Melanie Boerries, Marie Follo, Ulrich G. Hofmann, Simon P Behringer, Paulina Will, Nils Schallner, Vidhya M Ravi, Daniel Delev, Christian Fung, Jürgen Beck, Lea Vollmer, and Oliver Schnell
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Crosstalk (biology) ,Interleukin 10 ,Immunity ,Myeloid cells ,medicine ,Cancer research ,Biology ,medicine.disease ,Glioblastoma - Abstract
Despite recent advances in cancer immunotherapy, its efficacy in Glioblastoma (GBM) is limited due to poor understanding of molecular states and cellular plasticity of immune cells within the tumor microenvironment. Here, we combined spatial and single-cell transcriptomics of 47.284 immune cells, to map the potential cellular interactions leading to the immunosuppressive microenvironment and dysfunction of T cells. Computational approach identified a subset of IL10 releasing HMOX1+ myeloid cells which activates transcriptional programs towards a dysfunctional state in T cells, and was found to be localized within mesenchymal dominated subregions of the tumor. These findings were further validated by a human ex-vivo neocortical GBM model (n=6) coupled with patient derived peripheral T-cells. Finally, the dysfunctional transformation of T cells was shown to be rescued by JAK/STAT inhibition in both our model and in-vivo. We strongly believe that our findings would be the stepping stone towards successful development of immunotherapeutic approaches in GBM.
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- 2021
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6. Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference
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Vidhya M. Ravi, Paulina Will, Jan Kueckelhaus, Na Sun, Kevin Joseph, Henrike Salié, Jasmin von Ehr, Lea Vollmer, Jasim K. Benotmane, Nicolas Neidert, Marie Follo, Florian Scherer, Jonathan M Goeldner, Simon P. Behringer, Pamela Franco, Ulrich G. Hofmann, Christian Fung, Jürgen Beck, Roman Sankowski, Marco Prinz, Saskia Killmer, Bertram Bengsch, Axel Karl Walch, Daniel Delev, Oliver Schnell, and Dieter Henrik Heiland
- Abstract
Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies1–3. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.
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- 2021
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7. Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference
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Roman Sankowski, Saskia Killmer, Kevin Joseph, Henrike Salié, Jonathan M Goeldner, Vidhya M Ravi, Marie Follo, Nicolas Neidert, Na Sun, Ulrich G. Hofmann, Florian Scherer, Simon P Behringer, Jasim Kada Benotmane, Jan Kekelhaus, Daniel Delev, Oliver Schnell, Lea Vollmer, Christian Fung, Jürgen Beck, Dieter Henrik Heiland, Paulina Will, Bertram Bengsch, Marco Prinz, Pamela Franco, Jasmin von Ehr, and Axel Walch
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Transcriptome ,Tumor microenvironment ,medicine.anatomical_structure ,Glioma ,medicine ,Mass cytometry ,Copy-number variation ,Human brain ,Biology ,Stem cell ,Proteomics ,medicine.disease ,Neuroscience - Abstract
Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.
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- 2021
- Full Text
- View/download PDF
8. Lineage and Spatial Mapping of Glioblastoma-associated Immunity
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Vidhya M. Ravi, Nicolas Neidert, Paulina Will, Kevin Joseph, Julian P. Maier, Jan Kückelhaus, Lea Vollmer, Jonathan M Goeldner, Simon P. Behringer, Florian Scherer, Melanie Boerries, Marie Follo, Tobias Weiss, Daniel Delev, Julius Kernbach, Pamela Franco, Nils Schallner, Christine Dierks, Maria Stella Carro, Ulrich G. Hofmann, Christian Fung, Jürgen Beck, Roman Sankowski, Marco Prinz, Oliver Schnell, and Dieter Henrik Heiland
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Transcriptome ,Interleukin 10 ,medicine.anatomical_structure ,Myeloid ,Cytokine ,Immune system ,medicine.medical_treatment ,T cell ,Cell ,Mesenchymal stem cell ,medicine ,Biology ,Cell biology - Abstract
SummaryThe diversity of molecular states and cellular plasticity of immune cells in the glioblastoma environment is still poorly understood. Here, we performed scRNA sequencing of the immune compartment and mapped potential cellular interactions leading to an immunosuppressive microenvironment and dysfunction of T cells. Through inferring the dynamic adaptation during T cell activation, we identified three different terminal states with unique transcriptional programs. Modeling of driver genes for terminal T cell fate identified IL-10 signaling alterations in a subpopulation of HAVCR2(+) T cells. To explore in depth cellular interactions, we established an in-silico model by the integration of spatial transcriptomic and scRNA-sequencing, and identified a subset of HMOX1+ myeloid cells defined by IL10 release leading to T cell exhaustion. We found a spatial overlap between HMOX(+) myeloid and HAVCR2(+) T cells, suggesting that myeloid-lymphoid interaction causes immunosuppression present in tumor regions with enriched mesenchymal gene expression. Using human neocortical GBM model, coupled with patient-derived T cells, we confirmed that the functional interaction between myeloid and lymphoid cells, leads to a dysfunctional state of T cells. This IL-10 driven T cell exhaustion was found to be rescued by JAK/STAT inhibition. A comprehensive understanding of the cellular states and plasticity of lymphoid cells in GBM will aid towards successful immunotherapeutic approaches.
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- 2020
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9. ATF3 reduces migration capacity by regulation of matrix metalloproteinases via NF
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Jessica, Guenzle, Louisa J, Wolf, Nicklas W C, Garrelfs, Jonathan M, Goeldner, Nadja, Osterberg, Cora R, Schindler, Joseph E, Saavedra, and Astrid, Weyerbrock
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Article - Abstract
Glioblastoma is associated with poor survival and a high recurrence rate in patients due to inevitable uncontrolled infiltrative tumor growth. The elucidation of the molecular mechanisms may offer opportunities to prevent relapses. In this study we investigated the role of the activating transcription factor 3 (ATF3) in migration of GBM cells in vitro. RNA microarray revealed that gene expression of ATF3 is induced by a variety of chemotherapeutics and experimental agents such as the nitric oxide donor JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate). We found NFκB and STAT3 to be downstream targets inhibited by overexpression of ATF3. We demonstrate that ATF3 is directly involved in the regulation of matrix metalloproteinase expression and activation. Overexpression of ATF3 therefore leads to a significantly reduced migration capacity and induction of tissue inhibitors of matrix metalloproteinases. Our study for the first time identifies ATF3 as a potential novel therapeutic target in glioblastoma.
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- 2016
10. P08.16 ATF3 reduces migration capacity by regulation of matrix metalloproteinases in glioblastoma in vitro
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Astrid Weyerbrock, Jessica Guenzle, and Jonathan M Goeldner
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Cancer Research ,ATF3 ,Chemistry ,Gelatinase A ,RNA ,Matrix metalloproteinase ,medicine.disease ,Cell biology ,Oncology ,Glioma ,Gene expression ,medicine ,Neurology (clinical) ,Transcription factor ,Gene ,POSTER PRESENTATIONS - Abstract
Objective: Glioblastoma is associated with poor survival and a high recurrence rate in patients due to the inevitable uncontrolled infiltrative tumor growth. The elucidation of the molecular mechanisms may offer opportunities to prevent relapses. In this study we investigated the role of the activating transcription factor 3 (ATF3) in the context of experimental nitric oxide donor (NO) treatment with JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin- 1-yl]diazen-1-ium-1,2-diolate) on migration of GBM cells in vitro. Methods: RNA microarray was performed to identify ATF3 as one of the genes upregulated by experimental NO therapy in U87 glioma cells. To elucidate its role in tumor growth and treatment response of malignant gliomas, ATF3 was overexpressed by lentiviral transduction and expression of target genes STAT3 and NFκB was investigated by qRT-PCR, Western Blot and immunocytochemistry. The underlying molecular mechanisms of migration capacity and proliferation were studied by Western Blot, zymography, immunostaining and PCR while migration was assessed by wound closure and invasion assay. Results: RNA microarray revealed that gene expression of ATF3 is 15-fold upregulated after exposure to 15 µM JS-K for 48 h. We demonstrate that ATF3 is directly involved in the regulation of matrix metalloproteinase expression and activation. MMP2, 7 and 9 were downregulated and MMP2 activity was reduced by overexpression of ATF3. While stat3 was 2.5-fold upregulated in cells overexpressing ATF3, STAT3 was no longer phosphorylated. Even if the expression of nfκb is not affected by ATF3, NFκB accumulated in the cytoplasm and did not translocate by TNFα stimulation. Cells overexpressing ATF3 migrated 40% slower into the gap (p=0.02) and reduced invasive capability to 30% (p=0.00004). The proliferation rate was 2-fold reduced by ATF3 (p=0.003) after 72 h whereas the influence of NO on viability did not change. Conclusions: Overexpression of ATF3 leads to a significantly reduced migration and invasion capacity by induction of tissue inhibitors of matrix metalloproteinases. ATF3 is directly involved in expression and activation of MMPs as well as the oncogenic regulators STAT3 and NFκB. Our study highlights for the first time ATF3 as a potential novel therapeutic target and can therefore be important for specific anticancer therapy to overcome the high treatment resistance of glioblastoma.
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- 2017
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