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2. Abstract CT114: Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into phase 1 in RCC/NSCLC

Author

Diaz, Nieves, primary, Garratt, Holly, additional, Zemla-Brown, Aleksandra, additional, Dominguez, Maria, additional, Helmer, Eric, additional, Alt, Isabella, additional, Sehlke, Robert, additional, Hieger, Norbert, additional, Winkler-Penz, Thomas, additional, Boudesco, Christophe, additional, Vladimer, Gregory, additional, Wilde, Tom, additional, Evans, Philip, additional, Italiano, Antoine, additional, and Krams, Michael, additional

Published
2023
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3. Abstract 2151: Identification of transcript adenosine fingerprint to enrich for A2AR and PD-1 inhibition responders

Author

Alt, Isabella, primary, Sehlke, Robert, additional, Lobley, Anna, additional, Baumgaertler, Claudia, additional, Stulic, Maja, additional, Hackner, Klaus, additional, Dzurillova, Lucia, additional, Petru, Edgar, additional, Hadjari, Laudia, additional, Lafleur, Judith, additional, Singer, Josef, additional, Krall, Nikolaus, additional, Šufliarsky, Jozef, additional, Hefler, Lukas, additional, Füreder, Thorsten, additional, Taubert, Christina, additional, Payne, Andrew, additional, Boudesco, Christophe, additional, and Vladimer, Gregory Ian, additional

Published
2023
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4. Abstract 4956: Discovering novel targetable pathways by combining functional and multi-omic data from primary ovarian cancer samples

Author

Gutierrez-Perez, Irene, primary, Ergüner, Bekir, additional, Buphamalai, Pisanu, additional, Van Ham, Joost, additional, Heinz, Paul, additional, Aranha, Valentin, additional, Okumura, Rin, additional, Waltenberger, Elisabeth, additional, Alt, Isabella, additional, Baumgaertler, Claudia, additional, Stulic, Maja, additional, Petru, Edgar, additional, Minichsdorfer, Christoph, additional, Lafleur, Judith, additional, Hefler, Lukas, additional, Hadjari, Laudia, additional, Dzurillova, Lucia, additional, Sufliarsky, Jozef, additional, Krall, Nikolaus, additional, Füreder, Thorsten, additional, Vladimer, Gregory Ian, additional, Vilagos, Bojan, additional, and Sehlke, Robert, additional

Published
2023
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5. Abstract 1893: Deep learning supported high content analysis of primary patient samples identifies ALK inhibition as a novel mechanism of action in a subset of ovarian cancers

Author

Gutierrez-Perez, Irene, primary, Van Ham, Joost, additional, Aranha, Valentin, additional, Okumura, Rin, additional, Waltenberger, Elisabeth, additional, Alt, Isabella, additional, Baumgaertler, Claudia, additional, Stulic, Maja, additional, Petru, Edgar, additional, Minichsdorfer, Christoph, additional, Hefler, Lukas, additional, Lafleur, Judith, additional, Krall, Nikolaus, additional, Füreder, Thorsten, additional, Vladimer, Gregory Ian, additional, Sehlke, Robert, additional, and Vilagos, Bojan, additional

Published
2022
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7. NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation

Author

Huth, Michelle, Santini, Laura, Galimberti, Elena, Ramesmayer, Julia, Titz-Teixeira, Fabian, Sehlke, Robert, Oberhuemer, Michael, Stummer, Sarah, Herzog, Veronika, Garmhausen, Marius, Romeike, Merrit, Chugunova, Anastasia, Leesch, Friederike, Holcik, Laurenz, Weipoltshammer, Klara, Lackner, Andreas, Schoefer, Christian, von Haeseler, Arndt, Buecker, Christa, Pauli, Andrea, Ameres, Stefan L., Smith, Austin, Beyer, Andreas, Leeb, Martin, Huth, Michelle, Santini, Laura, Galimberti, Elena, Ramesmayer, Julia, Titz-Teixeira, Fabian, Sehlke, Robert, Oberhuemer, Michael, Stummer, Sarah, Herzog, Veronika, Garmhausen, Marius, Romeike, Merrit, Chugunova, Anastasia, Leesch, Friederike, Holcik, Laurenz, Weipoltshammer, Klara, Lackner, Andreas, Schoefer, Christian, von Haeseler, Arndt, Buecker, Christa, Pauli, Andrea, Ameres, Stefan L., Smith, Austin, Beyer, Andreas, and Leeb, Martin

Abstract

Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2(PTC)). NMD deficiency leads to translation of the truncated eIF4A2(PTC) protein. eIF4A2(PTC) elicits increased mTORC1 activity and translation rates and causes differentiation delays. This establishes a previously unknown feedback loop between NMD and translation initiation. Furthermore, our results show a clear hierarchy in the severity of target deregulation and differentiation phenotypes between NMD effector KOs (Smg5 KO > Smg6 KO > Smg7 KO), which highlights heterodimer-independent functions for SMG5 and SMG7. Together, our findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.

Published
2022

8. NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation

Author

Huth, Michelle, primary, Santini, Laura, additional, Galimberti, Elena, additional, Ramesmayer, Julia, additional, Titz-Teixeira, Fabian, additional, Sehlke, Robert, additional, Oberhuemer, Michael, additional, Stummer, Sarah, additional, Herzog, Veronika, additional, Garmhausen, Marius, additional, Romeike, Merrit, additional, Chugunova, Anastasia, additional, Leesch, Friederike, additional, Holcik, Laurenz, additional, Weipoltshammer, Klara, additional, Lackner, Andreas, additional, Schoefer, Christian, additional, von Haeseler, Arndt, additional, Buecker, Christa, additional, Pauli, Andrea, additional, Ameres, Stefan L., additional, Smith, Austin, additional, Beyer, Andreas, additional, and Leeb, Martin, additional

Published
2022
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9. Cooperative molecular networks drive a mammalian cell state transition

Author

Lackner, Andreas, Sehlke, Robert, Garmhausen, Marius, Stirparo, Giuliano Giuseppe, Huth, Michelle, Titz-Teixeira, Fabian, van der Lelij, Petra, Ramesmayer, Julia, Thomas, Henry Fabian, Ralser, Meryem, Santini, Laura, Sarov, Mihail, Stewart, A. Francis, Smith, Austin, Beyer, Andreas, and Leeb, Martin

Subjects
embryonic structures
Abstract

In the mammalian embryo, epiblast cells must exit their naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro . Here we employed a combination of genetic screens in haploid ESCs, CRISPR/Cas9 gene disruption, large-scale transcriptomics and computational systems-biology to delineate the regulatory circuits governing naïve state exit. Transcriptome profiles for 73 knockouts (KOs) predominantly manifest delays on the trajectory from naive to formative epiblast. We identified 374 naïve-associated genes (NAGs), which are tightly connected to the epiblast state and largely conserved in human stem cells and primate embryos. Integrated analysis of mutant transcriptomes revealed that the activity of multiple genes promoting pluripotency progression is funneled into discrete regulatory modules. We demonstrate that these modules are under control of five signaling pathways that operate in parallel to direct this pivotal mammalian cell state transition.

Published
2020
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10. Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Author

Tain, Luke Stephen, Sehlke, Robert, Meilenbrock, Ralf Leslie, Leech, Thomas, Paulitz, Jonathan, Chokkalingam, Manopriya, Nagaraj, Nagarjuna, Groenke, Sebastian, Froehlich, Jenny, Atanassov, Ilian, Mann, Matthias, Beyer, Andreas, Partridge, Linda, Tain, Luke Stephen, Sehlke, Robert, Meilenbrock, Ralf Leslie, Leech, Thomas, Paulitz, Jonathan, Chokkalingam, Manopriya, Nagaraj, Nagarjuna, Groenke, Sebastian, Froehlich, Jenny, Atanassov, Ilian, Mann, Matthias, Beyer, Andreas, and Partridge, Linda

Abstract

Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.

Published
2021

11. Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Author

Tain, Luke Stephen, primary, Sehlke, Robert, additional, Meilenbrock, Ralf Leslie, additional, Leech, Thomas, additional, Paulitz, Jonathan, additional, Chokkalingam, Manopriya, additional, Nagaraj, Nagarjuna, additional, Grönke, Sebastian, additional, Fröhlich, Jenny, additional, Atanassov, Ilian, additional, Mann, Matthias, additional, Beyer, Andreas, additional, and Partridge, Linda, additional

Published
2021
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12. Abstract 5233: Towards patient-centric drug discovery: Analyzing drug action in malignant pleural effusions and ascites using high content imaging and deep learning

Author

Sehlke, Robert, primary, Taubert, Christina, additional, Alt, Isabella, additional, Rohrer, Florian, additional, Fuchs, Elisabeth, additional, Vilagos, Bojan, additional, Krall, Nikolaus, additional, Christoph, Minichsdorfer, additional, Schumacher, Michael, additional, Maurer, Dominik, additional, Hackner, Klaus, additional, Lafleur, Judith, additional, Hefler, Lukas, additional, Fureder, Thorsten, additional, and Vladimer, Gregory Ian, additional

Published
2020
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13. Integration of molecular regulatory networks: The Drosophila insulin response and mouse embryonic stem cell differentiation dynamics

Author

Sehlke, Robert

Subjects
ddc:570, ddc:004
Abstract

Systems biology relies on considering processes on multiple levels of the organism—e.g. tissues, transcripts and proteins, developmental stages, and age—to generate and test hypotheses that are not amenable to a single-gene approach. This is of particular importance in ageing research, which deals with convoluted relationships between multiple disparate aspects of biology and medicine, as summarized recently in “The Hallmarks of Aging” (López-Otín et al. 2013). In this thesis, I present results from two large collaborative efforts that generated, integrated, and analysed systems level data. These projects focus on two of the nine hallmarks of ageing—deregulated nutrient sensing and stem cell exhaustion—, but touch on several others. The discovery of downstream processes of delayed ageing in Drosophila insulin mutants. This project is further subdivided into four major parts: The tissue-specific proteome response to reduced insulin in the mNSC-ablation model of reduced insulin signalling (IIS). Furthermore, the dependency of these changes on the transcription factor dFOXO. As published in (Tain et al. 2017). The comparison of the tissue-specific proteome responses of mNSC-ablated flies and a second model of reduced IIS, dilp2-3,5 mutant flies. Furthermore, the dependency of the dilp2-3,5 response on the presence of the endosymbiont Wolbachia. The role of post-transcriptional regulation in the tissue-specific proteome to reduced IIS response of dilp2-3,5 mutants, through the analysis of matching RNAseq data. The age-dependent proteome response to reduced IIS in dilp2-3,5 mutants. Presented are preliminary results from two tissues (fat body and thorax). Understanding mouse embryonic stem cell pluripotency and early differentiation. The focus of this project is the analysis of RNAseq data from 74 differentiation defect mESC lines under conditions promoting naive pluripotency or early differentiation. We also present supporting analysis of the specific effect of LIF on naive mESCs and insights from a screen of a inhibitor/knockout screen. As the project is ongoing, results presented in this thesis are preliminary. Additionally, the appendix describes custom R tools that were developed to facilitate the analysis, visualization of results, and collaboration for these projects: CellPlot, SETHRO, and mESCexplorer.

Published
2019

14. A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance

Author

Tain, Luke S., Sehlke, Robert, Jain, Chirag, Chokkalingam, Manopriya, Nagaraj, Nagarjuna, Essers, Paul, Rassner, Mark, Groenke, Sebastian, Froelich, Jenny, Dieterich, Christoph, Mann, Matthias, Alic, Nazif, Beyer, Andreas, Partridge, Linda, Tain, Luke S., Sehlke, Robert, Jain, Chirag, Chokkalingam, Manopriya, Nagaraj, Nagarjuna, Essers, Paul, Rassner, Mark, Groenke, Sebastian, Froelich, Jenny, Dieterich, Christoph, Mann, Matthias, Alic, Nazif, Beyer, Andreas, and Partridge, Linda

Abstract

Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.

Published
2017

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