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3. An Anticancer Rhenium Tricarbonyl Targets Fe-S Cluster Biogenesis in Ovarian Cancer Cells.

Author

Neuditschko, Benjamin, King, A, Huang, Zhouyang, Janker, Lukas, Bileck, Andrea, Borutzki, Yasmin, Marker, Sierra, Gerner, Christopher, Wilson, Justin, and Meier-Menches, Samuel

Subjects
Cancer, Mode of Action, Proteomics, Rhenium, Target Identification, Humans, Female, Rhenium, Iron-Sulfur Proteins, Mitochondria, Ovarian Neoplasms, Ferritins
Abstract

Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose-dependent targets with concentrations of competitive saturation between 0.1 and 32 μM despite the broad proteotoxic effects of TRIP. Target-response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.

Published
2022

5. Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation

Author

de Jonckheere, Bianca, Kollotzek, Ferdinand, Münzer, Patrick, Göb, Vanessa, Fischer, Melina, Mott, Kristina, Coman, Cristina, Troppmair, Nina Nicole, Manke, Mailin-Christin, Zdanyte, Monika, Harm, Tobias, Sigle, Manuel, Kopczynski, Dominik, Bileck, Andrea, Gerner, Christopher, Hoffmann, Nils, Heinzmann, David, Assinger, Alice, Gawaz, Meinrad, Stegner, David, Schulze, Harald, Borst, Oliver, and Ahrends, Robert

Published
2023
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9. Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis

Author

Fetahu, Irfete S., Esser-Skala, Wolfgang, Dnyansagar, Rohit, Sindelar, Samuel, Rifatbegovic, Fikret, Bileck, Andrea, Skos, Lukas, Bozsaky, Eva, Lazic, Daria, Shaw, Lisa, Tötzl, Marcus, Tarlungeanu, Dora, Bernkopf, Marie, Rados, Magdalena, Weninger, Wolfgang, Tomazou, Eleni M., Bock, Christoph, Gerner, Christopher, Ladenstein, Ruth, Farlik, Matthias, Fortelny, Nikolaus, and Taschner-Mandl, Sabine

Published
2023
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10. Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

Author

Ries, Alexander, Flehberger, Daniela, Slany, Astrid, Pirker, Christine, Mader, Johanna C., Mohr, Thomas, Schelch, Karin, Sinn, Katharina, Mosleh, Berta, Hoda, Mir Alireza, Dome, Balazs, Dolznig, Helmut, Krupitza, Georg, Müllauer, Leonhard, Gerner, Christopher, Berger, Walter, and Grusch, Michael

Published
2023
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15. Author Correction: Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation

Author

de Jonckheere, Bianca, Kollotzek, Ferdinand, Münzer, Patrick, Göb, Vanessa, Fischer, Melina, Mott, Kristina, Coman, Cristina, Troppmair, Nina Nicole, Manke, Mailin-Christin, Zdanyte, Monika, Harm, Tobias, Sigle, Manuel, Kopczynski, Dominik, Bileck, Andrea, Gerner, Christopher, Hoffmann, Nils, Heinzmann, David, Assinger, Alice, Gawaz, Meinrad, Stegner, David, Schulze, Harald, Borst, Oliver, and Ahrends, Robert

Published
2023
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17. Automated High-Throughput Biological Sex Identification from Archeological Human Dental Enamel Using Targeted Proteomics.

Author

Koenig, Claire, Bortel, Patricia, Paterson, Ryan S., Rendl, Barbara, Madupe, Palesa P., Troché, Gaudry B., Hermann, Nuno Vibe, Martínez de Pinillos, Marina, Martinón-Torres, María, Mularczyk, Sandra, Schjellerup Jørkov, Marie Louise, Gerner, Christopher, Kanz, Fabian, Martinez-Val, Ana, Cappellini, Enrico, and Olsen, Jesper V.

Published
2024
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27. RiboScreen TM Technology Delivers a Ribosomal Target and a Small-Molecule Ligand for Ribosome Editing to Boost the Production Levels of Tropoelastin, the Monomeric Unit of Elastin.

Author

Wimmer, Bjoern, Schernthaner, Jan, Edobor, Genevieve, Friedrich, Andreas, Poeltner, Katharina, Temaj, Gazmend, Wimmer, Marlies, Kronsteiner, Elli, Pichler, Mara, Gercke, Hanna, Huber, Ronald, Kaefer, Niklas, Rinnerthaler, Mark, Karl, Thomas, Krauß, Jan, Mohr, Thomas, Gerner, Christopher, Hintner, Helmut, Breitenbach, Michael, and Bauer, Johann W.

Subjects
CYTOSKELETAL proteins, SMALL molecules, DRUG discovery, TOPICAL drug administration, ELASTIN
Abstract

Elastin, a key structural protein essential for the elasticity of the skin and elastogenic tissues, degrades with age. Replenishing elastin holds promise for anti-aging cosmetics and the supplementation of elastic activities of the cardiovascular system. We employed RiboScreenTM, a technology for identifying molecules that enhance the production of specific proteins, to target the production of tropoelastin. We make use of RiboScreenTM in two crucial steps: first, to pinpoint a target ribosomal protein (TRP), which acts as a switch to increase the production of the protein of interest (POI), and second, to identify small molecules that activate this ribosomal protein switch. Using RiboScreenTM, we identified ribosomal protein L40, henceforth eL40, as a TRP switch to boost tropoelastin production. Drug discovery identified a small-molecule hit that binds to eL40. In-cell treatment demonstrated activity of the eL40 ligand and delivered increased tropoelastin production levels in a dose-dependent manner. Thus, we demonstrate that RiboScreenTM can successfully identify a small-molecule hit capable of selectively enhancing tropoelastin production. This compound has the potential to be developed for topical or systemic applications to promote skin rejuvenation and to supplement elastic functionality within the cardiovascular system. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Memory effects of prior subculture may impact the quality of multiomic perturbation profiles.

Author

Bortel, Patricia, Hagn, Gerhard, Skos, Lukas, Bileck, Andrea, Paulitschke, Verena, Paulitschke, Philipp, Gleiter, Lion, Mohr, Thomas, Gerner, Christopher, and Meier-Menches, Samuel M.

Subjects
BIOLOGICAL systems, MULTIOMICS, REAL-time control, PHARMACODYNAMICS, CELL growth
Abstract

Mass spectrometry-based omics technologies are increasingly used in perturbation studies to map drug effects to biological pathways by identifying significant molecular events. Significance is influenced by fold change and variation of each molecular parameter, but also by multiple testing corrections. While the fold change is largely determined by the biological system, the variation is determined by experimental workflows. Here, it is shown that memory effects of prior subculture can influence the variation of perturbation profiles using the two colon carcinoma cell lines SW480 and HCT116. These memory effects are largely driven by differences in growth states that persist into the perturbation experiment. In SW480 cells, memory effects combined with moderate treatment effects amplify the variation in multiple omics levels, including eicosadomics, proteomics, and phosphoproteomics. With stronger treatment effects, the memory effect was less pronounced, as demonstrated in HCT116 cells. Subculture homogeneity was controlled by real-time monitoring of cell growth. Controlled homogeneous subculture resulted in a perturbation network of 321 causal conjectures based on combined proteomic and phosphoproteomic data, compared to only 58 causal conjectures without controlling subculture homogeneity in SW480 cells. Some cellular responses and regulatory events were identified that extend the mode of action of arsenic trioxide (ATO) only when accounting for these memory effects. Controlled prior subculture led to the finding of a synergistic combination treatment of ATO with the thioredoxin reductase 1 inhibitor auranofin, which may prove useful in the management of NRF2-mediated resistance mechanisms. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Silica nanoparticle conjugation with gallic acid towards enhanced free radical scavenging capacity and activity on osteosarcoma cells in vitro.

Author

Hohagen, Mariam, Saraiva, Nuno, Kählig, Hanspeter, Gerner, Christopher, Del Favero, Giorgia, and Kleitz, Freddy

Abstract

Gallic acid (GA), derived from land plants, possesses diverse physiological benefits, including anti-inflammatory and anticancer effects, making it valuable for biomedical applications. In this study, GA was used to modify the surface of dendritic mesoporous silica nanoparticles (DMSNs) via carbamate (DMSN-NCO-GA) or amide (DMSN-NH-GA) bonds, using a post-grafting technique. To explore GA-conjugated materials' potential in modulating cancer cell redox status, three variants of osteosarcoma cells (U2-OS) were used. These variants comprised the wild-type cells (NEO), the cells overexpressing the wild-type human Golgi anti-apoptotic protein (hGAAP), and the null mutant of hGAAP (Ct-mut), as this protein was previously demonstrated to play a role in intracellular reactive oxygen species (ROS) accumulation and cell migration. In the absence of external ROS triggers, non-modified DMSNs increased intracellular ROS in Ct-mut and NEO cells, while GA-conjugated materials, particularly DMSN-NH-GA, significantly reduced ROS levels, especially pronounced with higher GA concentrations and notably in hGAAP cells with inherently higher ROS levels. Additionaly, NH-GA conjugates were less cytotoxic, more effective in reducing cell migration, and had higher ROS buffering capacity compared to DMSN-NCO-GA materials. However, in the presence of the external stressor tert-butyl-hydroperoxide (TBHP), NCO-GA conjugates showed more efficient reduction of intracellular ROS. These findings suggest that varying chemical decoration strategies of nanomaterials, along with the accessibility of functional groups to the cellular environment, significantly influence the biological response in osteosarcoma cells. Highlighting this, GA-conjugation is a promising method for implementing antioxidant properties and inhibiting cancer cell migration, warranting further research in anticancer treatment and drug development. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Automated high-throughput biological sex identification from archaeological human dental enamel using targeted proteomics

Author

Koenig, Claire, primary, Bortel, Patricia, additional, Paterson, Ryan S., additional, Rendl, Barbara, additional, Madupe, Palesa P., additional, Troché, Gaudry B., additional, Hermann, Nuno Vibe, additional, Martínez de Pinillos, Marina, additional, Martinón-Torres, María, additional, Mularczyk, Sandra, additional, Jørkov, Marie Louise Schjellerup, additional, Gerner, Christopher, additional, Kanz, Fabian, additional, Martinez-Val, Ana, additional, Cappellini, Enrico, additional, and Olsen, Jesper V., additional

Published
2024
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31. Data from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy

Author

Zila, Nina, primary, Eichhoff, Ossia M., primary, Steiner, Irene, primary, Mohr, Thomas, primary, Bileck, Andrea, primary, Cheng, Phil F., primary, Leitner, Alexander, primary, Gillet, Ludovic, primary, Sajic, Tatjana, primary, Goetze, Sandra, primary, Friedrich, Betty, primary, Bortel, Patricia, primary, Strobl, Johanna, primary, Reitermaier, René, primary, Hogan, Sabrina A., primary, Martínez Gómez, Julia M., primary, Staeger, Ramon, primary, Tuchmann, Felix, primary, Peters, Sophie, primary, Stary, Georg, primary, Kuttke, Mario, primary, Elbe-Bürger, Adelheid, primary, Hoeller, Christoph, primary, Kunstfeld, Rainer, primary, Weninger, Wolfgang, primary, Wollscheid, Bernd, primary, Dummer, Reinhard, primary, French, Lars E., primary, Gerner, Christopher, primary, Aebersold, Ruedi, primary, Levesque, Mitchell P., primary, and Paulitschke, Verena, primary

Published
2024
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32. Supplementary Fig. S2 from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy

Author

Zila, Nina, primary, Eichhoff, Ossia M., primary, Steiner, Irene, primary, Mohr, Thomas, primary, Bileck, Andrea, primary, Cheng, Phil F., primary, Leitner, Alexander, primary, Gillet, Ludovic, primary, Sajic, Tatjana, primary, Goetze, Sandra, primary, Friedrich, Betty, primary, Bortel, Patricia, primary, Strobl, Johanna, primary, Reitermaier, René, primary, Hogan, Sabrina A., primary, Martínez Gómez, Julia M., primary, Staeger, Ramon, primary, Tuchmann, Felix, primary, Peters, Sophie, primary, Stary, Georg, primary, Kuttke, Mario, primary, Elbe-Bürger, Adelheid, primary, Hoeller, Christoph, primary, Kunstfeld, Rainer, primary, Weninger, Wolfgang, primary, Wollscheid, Bernd, primary, Dummer, Reinhard, primary, French, Lars E., primary, Gerner, Christopher, primary, Aebersold, Ruedi, primary, Levesque, Mitchell P., primary, and Paulitschke, Verena, primary

Published
2024
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33. Supplementary Table S1 from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy

Author

Zila, Nina, primary, Eichhoff, Ossia M., primary, Steiner, Irene, primary, Mohr, Thomas, primary, Bileck, Andrea, primary, Cheng, Phil F., primary, Leitner, Alexander, primary, Gillet, Ludovic, primary, Sajic, Tatjana, primary, Goetze, Sandra, primary, Friedrich, Betty, primary, Bortel, Patricia, primary, Strobl, Johanna, primary, Reitermaier, René, primary, Hogan, Sabrina A., primary, Martínez Gómez, Julia M., primary, Staeger, Ramon, primary, Tuchmann, Felix, primary, Peters, Sophie, primary, Stary, Georg, primary, Kuttke, Mario, primary, Elbe-Bürger, Adelheid, primary, Hoeller, Christoph, primary, Kunstfeld, Rainer, primary, Weninger, Wolfgang, primary, Wollscheid, Bernd, primary, Dummer, Reinhard, primary, French, Lars E., primary, Gerner, Christopher, primary, Aebersold, Ruedi, primary, Levesque, Mitchell P., primary, and Paulitschke, Verena, primary

Published
2024
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42. Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy

Author

Zila, Nina, primary, Eichhoff, Ossia M., additional, Steiner, Irene, additional, Mohr, Thomas, additional, Bileck, Andrea, additional, Cheng, Phil F., additional, Leitner, Alexander, additional, Gillet, Ludovic, additional, Sajic, Tatjana, additional, Goetze, Sandra, additional, Friedrich, Betty, additional, Bortel, Patricia, additional, Strobl, Johanna, additional, Reitermaier, René, additional, Hogan, Sabrina A., additional, Martínez Gómez, Julia M., additional, Staeger, Ramon, additional, Tuchmann, Felix, additional, Peters, Sophie, additional, Stary, Georg, additional, Kuttke, Mario, additional, Elbe-Bürger, Adelheid, additional, Hoeller, Christoph, additional, Kunstfeld, Rainer, additional, Weninger, Wolfgang, additional, Wollscheid, Bernd, additional, Dummer, Reinhard, additional, French, Lars E., additional, Gerner, Christopher, additional, Aebersold, Ruedi, additional, Levesque, Mitchell P., additional, and Paulitschke, Verena, additional

Published
2023
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43. En route to targeted ribosome editing to replenish skin anchor protein Lamβ3 in Junctional Epidermolysis Bullosa

Author

Wimmer, Bjoern, primary, Friedrich, Andreas, additional, Poeltner, Katharina, additional, Edobor, Genevieve, additional, Mosshammer, Claudia, additional, Temaj, Gazmend, additional, Rathner, Adriana, additional, Karl, Thomas, additional, Krauss, Jan, additional, von Hagen, Joerg, additional, Gerner, Christopher, additional, Breitenbach, Michael, additional, Hintner, Helmut, additional, Bauer, Johannes W., additional, and Breitenbach-Koller, Hannelore, additional

Published
2023
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45. Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity

Author

Liszt, Kathrin I., Wang, Qiaoling, Farhadipour, Mona, Segers, Anneleen, Thijs, Theo, Nys, Linda, Deleus, Ellen, Van der Schueren, Bart, Gerner, Christopher, Neuditschko, Benjamin, Ceulemans, Laurens J., Lannoo, Matthias, Tack, Jan, and Depoortere, Inge

Subjects
Obesity -- Prevention, Intestines -- Physiological aspects, Taste buds -- Physiological aspects -- Health aspects -- Genetic aspects, Natural immunity -- Health aspects -- Genetic aspects, Health care industry
Abstract

Bitter taste receptors (taste 2 receptors, TAS2Rs) serve as warning sensors in the lingual system against the ingestion of potentially poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially those from individuals with obesity, responded to bitter agonists by inducing the release of antimicrobial peptides ([alpha]-defensin 5 and regenerating islet-derived protein 3 [alpha] [REG3A]) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. We found that the effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 deletion polymorphisms and thus confirmed a role for TAS2R43. RNA-Seq revealed that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and LDLR, genes that are involved in anorectic signaling and lipid homeostasis. In conclusion, TAS2Rs in the intestine constitute a promising target for treating diseases that involve disturbances in the innate immune system and body weight control. TAS2R polymorphisms may be valuable genetic markers to predict therapeutic responses., Introduction Bitter is an aversive taste perceived on the tongue that acts as the first defense mechanism to protect our body against the ingestion of potentially poisonous compounds (1). Bitter [...]

Published
2022
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46. Selective Arylation of Selenocysteine of Thioredoxin Reductase 1 by an Organogold Compound: Expanding the Tool-Box of Metal-Templated Reactions in Cancer Cells

Author

Skos, Lukas, primary, Schmidt, Claudia, additional, Thomas, Sophie, additional, Park, Mihyun, additional, Bonsignore, Riccardo, additional, Del Favero, Giorgia, additional, Mohr, Thomas, additional, Bileck, Andrea, additional, Gerner, Christopher, additional, Casini, Angela, additional, and Meier-Menches, Samuel M., additional

Published
2023
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47. Primary and hTERT-Transduced Mesothelioma-Associated Fibroblasts but Not Primary or hTERT-Transduced Mesothelial Cells Stimulate Growth of Human Mesothelioma Cells

Author

Ries, Alexander, primary, Slany, Astrid, additional, Pirker, Christine, additional, Mader, Johanna C., additional, Mejri, Doris, additional, Mohr, Thomas, additional, Schelch, Karin, additional, Flehberger, Daniela, additional, Maach, Nadine, additional, Hashim, Muhammad, additional, Hoda, Mir Alireza, additional, Dome, Balazs, additional, Krupitza, Georg, additional, Berger, Walter, additional, Gerner, Christopher, additional, Holzmann, Klaus, additional, and Grusch, Michael, additional

Published
2023
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