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2. Figure S1 from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Author

Mohme, Malte, primary, Maire, Cecile L., primary, Geumann, Ulf, primary, Schliffke, Simon, primary, Dührsen, Lasse, primary, Fita, Krystian, primary, Akyüz, Nuray, primary, Binder, Mascha, primary, Westphal, Manfred, primary, Guenther, Christine, primary, Lamszus, Katrin, primary, Hermann, Felix G., primary, and Schmidt, Nils Ole, primary

Published
2023
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3. Supplementary Information from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Author

Mohme, Malte, primary, Maire, Cecile L., primary, Geumann, Ulf, primary, Schliffke, Simon, primary, Dührsen, Lasse, primary, Fita, Krystian, primary, Akyüz, Nuray, primary, Binder, Mascha, primary, Westphal, Manfred, primary, Guenther, Christine, primary, Lamszus, Katrin, primary, Hermann, Felix G., primary, and Schmidt, Nils Ole, primary

Published
2023
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4. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice

Author

Weber, Julia, Öllinger, Rupert, Friedrich, Mathias, Ehmer, Ursula, Barenboim, Maxim, Steiger, Katja, Heid, Irina, Mueller, Sebastian, Maresch, Roman, Engleitner, Thomas, Gross, Nina, Geumann, Ulf, Fu, Beiyuan, Segler, Angela, Yuan, Detian, Lange, Sebastian, Strong, Alexander, de la Rosa, Jorge, Esposito, Irene, Liu, Pentao, Cadiñanos, Juan, Vassiliou, George S., Schmid, Roland M., Schneider, Günter, Unger, Kristian, Yang, Fengtang, Braren, Rickmer, Heikenwälder, Mathias, Varela, Ignacio, Saur, Dieter, Bradley, Allan, and Rad, Roland

Published
2015

5. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, Rad, Lena, Wang, Wei, Strong, Alexander, Ponstingl, Hannes, Bronner, Iraad F, Mayho, Matthew, Steiger, Katja, Weber, Julia, Hieber, Maren, Veltkamp, Christian, Eser, Stefan, Geumann, Ulf, Öllinger, Rupert, Zukowska, Magdalena, Barenboim, Maxim, Maresch, Roman, Cadiñanos, Juan, Friedrich, Mathias, Varela, Ignacio, Constantino-Casas, Fernando, Sarver, Aaron, ten Hoeve, Jelle, Prosser, Haydn, Seidler, Barbara, Bauer, Judith, Heikenwälder, Mathias, Metzakopian, Emmanouil, Krug, Anne, Ehmer, Ursula, Schneider, Günter, Knösel, Thomas, Rümmele, Petra, Aust, Daniela, Grützmann, Robert, Pilarsky, Christian, Ning, Zemin, Wessels, Lodewyk, Schmid, Roland M, Quail, Michael A, Vassiliou, George, Esposito, Irene, Liu, Pentao, Saur, Dieter, and Bradley, Allan

Published
2015
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6. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice

Author

Maresch, Roman, Mueller, Sebastian, Veltkamp, Christian, Öllinger, Rupert, Friedrich, Mathias, Heid, Irina, Steiger, Katja, Weber, Julia, Engleitner, Thomas, Barenboim, Maxim, Klein, Sabine, Louzada, Sandra, Banerjee, Ruby, Strong, Alexander, Stauber, Teresa, Gross, Nina, Geumann, Ulf, Lange, Sebastian, Ringelhan, Marc, Varela, Ignacio, Unger, Kristian, Yang, Fengtang, Schmid, Roland M., Vassiliou, George S., Braren, Rickmer, Schneider, Günter, Heikenwalder, Mathias, Bradley, Allan, Saur, Dieter, and Rad, Roland

Published
2016
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8. Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Author

Mohme, Malte, primary, Maire, Cecile L., additional, Geumann, Ulf, additional, Schliffke, Simon, additional, Dührsen, Lasse, additional, Fita, Krystian, additional, Akyüz, Nuray, additional, Binder, Mascha, additional, Westphal, Manfred, additional, Guenther, Christine, additional, Lamszus, Katrin, additional, Hermann, Felix G., additional, and Schmidt, Nils Ole, additional

Published
2020
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11. IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells

Author

Hombach, Andreas A., Geumann, Ulf, Guenther, Christine, Hermann, Felix G., Abken, Hinrich, Hombach, Andreas A., Geumann, Ulf, Guenther, Christine, Hermann, Felix G., and Abken, Hinrich

Abstract

Chimeric antigen receptor (CAR) redirected T cells are efficacious in the treatment of leukemia/lymphoma, however, showed less capacities in eliminating solid tumors which is thought to be partly due to the lack of cytokine support in the tumor lesion. In order to deliver supportive cytokines, we took advantage of the inherent ability of mesenchymal stem cells (MSCs) to actively migrate to tumor sites and engineered MSCs to release both IL7 and IL12 to promote homeostatic expansion and Th1 polarization. There is a mutual interaction between engineered MSCs and CAR T cells; in presence of CAR T cell released IFN-gamma and TNF-alpha, chronic inflammatory Th2 MSCs shifted towards a Th17/Th1 pattern with IL2 and IL15 release that mutually activated CAR T cells with extended persistence, amplification, killing and protection from activation induced cell death. MSCs releasing IL7 and IL12 were superior over non-modified MSCs in supporting the CAR T cell response and improved the anti-tumor attack in a transplant tumor model. Data demonstrate the first use of genetically modified MSCs as vehicles to deliver immuno-modulatory proteins to the tumor tissue in order to improve the efficacy of CAR T cells in the treatment of solid malignancies.

Published
2020

12. Intracerebral immunmodulation by IL12/IL7-expressing mesenchymal stem cells induces long-term survival and immunity in glioblastoma

Author

Schmidt, Nils Ole, Mohme, Malte, Geumann, Ulf, Dührsen, Lasse, Maire, Cecile, Günther, Christine, Westphal, Manfred, and Hermann, Felix

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Objective: Mesenchymal stem cells (MSC) show an inherent brain tumor cell tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile stem cell-based local immunmodulation is able to overcome the immunosuppressive GBM microenvironment and[for full text, please go to the a.m. URL], 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Published
2018
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13. IMMU-55. IMMUNOMODULATORY IL-7 AND IL-12-EXPRESSING MSCs INDUCE LONG-TERM SURVIVAL AND IMMUNITY IN SYNGENEIC INTRACEREBRAL GLIOBLASTOMA MODELS

Author

Mohme, Malte, primary, Maire, Cecile, additional, Geumann, Ulf, additional, Dührsen, Lasse, additional, Schliffke, Simon, additional, Fita, Krystian, additional, Binder, Mascha, additional, Lamszus, Katrin, additional, Guenther, Christine, additional, Westphal, Manfred, additional, Hermann, Felix, additional, and Schmidt, Nils Ole, additional

Published
2018
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14. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, primary, Rad, Lena, additional, Wang, Wei, additional, Strong, Alexander, additional, Ponstingl, Hannes, additional, Bronner, Iraad F, additional, Mayho, Matthew, additional, Steiger, Katja, additional, Weber, Julia, additional, Hieber, Maren, additional, Veltkamp, Christian, additional, Eser, Stefan, additional, Geumann, Ulf, additional, Öllinger, Rupert, additional, Zukowska, Magdalena, additional, Barenboim, Maxim, additional, Maresch, Roman, additional, Cadiñanos, Juan, additional, Friedrich, Mathias, additional, Varela, Ignacio, additional, Constantino-Casas, Fernando, additional, Sarver, Aaron, additional, ten Hoeve, Jelle, additional, Prosser, Haydn, additional, Seidler, Barbara, additional, Bauer, Judith, additional, Heikenwälder, Mathias, additional, Metzakopian, Emmanouil, additional, Krug, Anne, additional, Ehmer, Ursula, additional, Schneider, Günter, additional, Knösel, Thomas, additional, Rümmele, Petra, additional, Aust, Daniela, additional, Grützmann, Robert, additional, Pilarsky, Christian, additional, Ning, Zemin, additional, Wessels, Lodewyk, additional, Schmid, Roland M, additional, Quail, Michael A, additional, Vassiliou, George, additional, Esposito, Irene, additional, Liu, Pentao, additional, Saur, Dieter, additional, and Bradley, Allan, additional

Published
2014
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15. Conformational constraining of inactive and active States of a seven transmembrane receptor by metal ion site engineering in the extracellular end of transmembrane segment V

Author

Rosenkilde, Mette M, David, Ralf, Oerlecke, Ilka, Benned-Jensen, Tau, Geumann, Ulf, Beck-Sickinger, Anette G, Schwartz, Thue W, Rosenkilde, Mette M, David, Ralf, Oerlecke, Ilka, Benned-Jensen, Tau, Geumann, Ulf, Beck-Sickinger, Anette G, and Schwartz, Thue W

Abstract

Udgivelsesdato: 2006-Dec, The extracellular part of transmembrane segment V (TM-V) is expected to be involved in the activation process of 7TM receptors, but its role is far from clear. Here, we study the highly constitutively active CXC-chemokine receptor encoded by human herpesvirus 8 (ORF74-HHV8), in which a metal ion site was introduced at the extracellular end of TM-V by substitution of two arginines at positions V:01 and V:05 with histidines [R208H; R212H]. The metal ion site conferred high-potency inverse agonist properties (EC(50), 1.7 microM) to Zn(II) in addition to agonist and allosteric enhancing properties at concentrations >10 microM. The chemokine interaction with [R208H;R212H]-ORF74 was altered compared with wild-type ORF74-HHV8 with decreased agonist (CXCL1/GROalpha) potency (84-fold), affinity (5.8- and 136-fold in competition against agonist and inverse agonist, respectively), and binding capacity (B(max); 25-fold). Zn(II) in activating concentrations (100 microM) acted as an allosteric enhancer as it increased the B(max) (7.1-fold), the potency (9.9-fold), the affinity (1.7- and 6.1-fold in competition against agonist and inverse agonist, respectively), and the efficacy (2.5-fold) of CXCL1/GROalpha. The activating properties of Zn(II) were not due to a metal ion site between the ligand and the receptor because CXCL1/GROalpha analogs in which the putative metal-ion binding residues had been substituted-[H19A] and [H34A]-acted like wild-type CXCL1/GROalpha. Based on the complex action of Zn(II) and on the chemokine interaction for [R208H;R212H]-ORF74, we conclude that the extracellular end of TM-V is important for the activation of this CXC-chemokine receptor.

Published
2006

16. The invariant chain transports TNF family member CD70 to MHC class II compartments in dendritic cells

Author

Zwart, Wilbert, primary, Peperzak, Victor, additional, de Vries, Evert, additional, Keller, Anna M., additional, van der Horst, Gerda, additional, Veraar, Elise A. M., additional, Geumann, Ulf, additional, Janssen, Hans, additional, Janssen, Lennert, additional, Naik, Shalin H., additional, Neefjes, Jacques, additional, and Borst, Jannie, additional

Published
2010
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20. Synaptic membrane proteins form stable microdomains in early endosomes.

Author

Geumann, Ulf, Schäfer, Christina, Riedel, Dietmar, Jahn, Reinhard, and Rizzoli, Silvio O.

Abstract

In the plasma membrane, membrane proteins are frequently organized in microdomains that are stabilized both by protein-protein and protein-lipid interactions, with the membrane lipid cholesterol being instrumental for microdomain stability. However, it is unclear whether such microdomains persist during endocytotic membrane trafficking. We used stimulated emission-depletion microscopy to investigate the domain structure of the endosomes. We developed a semiautomatic method for counting the individual domains, an approach that we have validated by immunoelectron microscopy. We found that in endosomes derived from neuroendocrine PC12 cells synaptophysin and several SNARE proteins are organized in microdomains. Cholesterol depletion by methyl-β-cyclodextrin disintegrates most of the domains. Interestingly, no change in the frequency of microdomains was observed when endosomes were fused with protein-free liposomes of similar size (in what constitutes a novel approach in modifying acutely the lipid composition of organelles), regardless of whether the membrane lipid composition of the liposomes was similar or very different from that of the endosomes. Similarly, Rab depletion from the endosome membranes left the domain structure unaffected. Furthermore, labeled exogenous protein, introduced into endosomes by liposome fusion, equilibrated with the corresponding microdomains. We conclude that synaptic membrane proteins are organized in stable but dynamic clusters within endosomes, which are likely to persist during membrane recycling. Microsc. Res. Tech. 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2010
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21. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice

Author

Maresch, Roman, Mueller, Sebastian, Veltkamp, Christian, Öllinger, Rupert, Friedrich, Mathias, Heid, Irina, Steiger, Katja, Weber, Julia, Engleitner, Thomas, Barenboim, Maxim, Klein, Sabine, Louzada, Sandra, Banerjee, Ruby, Strong, Alexander, Stauber, Teresa, Gross, Nina, Geumann, Ulf, Lange, Sebastian, Ringelhan, Marc, Varela, Ignacio, Unger, Kristian, Yang, Fengtang, Schmid, Roland M, Vassiliou, George S, Braren, Rickmer, Schneider, Günter, Heikenwalder, Mathias, Bradley, Allan, Saur, Dieter, and Rad, Roland

Subjects
BRCA2 Protein, Genome, Carcinogenesis, High-Throughput Nucleotide Sequencing, Neoplasms, Experimental, Sequence Analysis, DNA, Transfection, Immunohistochemistry, Magnetic Resonance Imaging, Polymerase Chain Reaction, Translocation, Genetic, 3. Good health, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, Electroporation, Mutation, Animals, CRISPR-Cas Systems, Chromosome Deletion, Genetic Engineering, Pancreas, Phylogeny
Abstract

Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research.

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