Cell Biology and Applied Systems Biology

Prof. Markus Morrison (Rehm)

Prof. Morrison (Rehm) is Director of the Institute of Cell Biology and Immunology and of the Stuttgart Research Center Systems Biology at the University of Stuttgart. Prof Morrison is member of the European Cell Death Organization and the European Association of Systems Medicine.

Research Overview

We are interested in the complexity of cellular signal transduction that controls cell fate decisions between death and survival. The underlying molecular processes and their perturbation have profound implications in health and disease and can form the basis for the identification of therapeutic intervention points. We therefore not only aim to obtain fundamental insight into the regulation of molecularly controlled cell death processes but also develop novel cell biological tools and mathematical models that assist us in describing and predicting the efficacy of novel drugs and drug combinations for the treatment of cancer. Our team is profoundly interdisciplinary and combines a wide array of techniques from the fields of cell biology, biochemistry, biophysics, bioinformatics and systems biology. Besides addressing fundamental research questions, we collaborate with clinical and private sector partners across Europe to translate our findings into innovative tools and applications for the benefit of the public.

Current major research consortia and collaboration partners:

 

 

Vacancies:

BSc/MSc thesis work: Places are limited. Students interested in conducting research projects towards a BSc or MSc thesis should get in touch at an early stage.

PhD/Doctoral thesis, Postdoctoral positions: Vacancies are advertised on the institute website and on EURAXESS. We are happy to support highly qualified and competitive candidates that wish to apply for fellowship funding programs to join our research team.

Requirements: We are looking for highly motivated, passionate candidates with a strong work ethic that pay attention to accuracy and precision. Prior experience in either experimental or mathematical methodologies relevant for our research programs is beneficial. Our team is very international and interdisciplinary, so we expect a willingness to interact and communicate across cultural and disciplinary boundaries within our institute and with our international collaborators.

Cellular Stress and Cell Death Decisions

Our cells continuously experience stress, and billions of cells decide to die within each of us every day. In our cells, complex molecular signaling networks sense and integrate complex stress signals and convert these into binary decisions between death and survival. Failure to activate molecular signaling networks that culminate in cell death is a hallmark of proliferative diseases such as cancer, whereas excessive cell death manifests in degenerative diseases.

We aim to understand the intricate balance between death and survival decisions at the tissue, cellular and molecular level. Knowledge about the mechanisms underlying stress sensing and death decisions in health and disease not only provides us with novel insight into fundamental biological processes but also paves the way for targeted interventions that can enhance or prevent cell death. Ultimately, this provides us with biologically defined rationales for the development and testing of novel therapeutics.

Insight into cellular decision making at the level of signaling systems

How can cells convert complex, analogue stress signals and therapeutic perturbations into strict and irreversible death decisions? Interestingly, the molecular interplay at the level of entire signaling systems controls these decisions, rather than individual genes or proteins. We therefore study signal transduction and decision making within the complexity of its natural context. In particular, we use high-end microscopy applications and specific fluorescent reporters to study signal transduction in real time inside of individual living cells. In addition, we develop mathematical models (deterministic, stochastic, data-driven) to simulate and better understand the intricate, non-linear signaling that governs cell death decisions. In combination, these approaches also assist us in identifying optimal intervention points to modulate or re-activate cell death processes where these are no longer functioning. This paves the way for the future optimization and personalization of treatments based on systems-level signal transduction knowledge, with particular use cases in the field of cancer therapy.

From Mechanisms to Applications

Can knowledge on cellular decision making assist us in better prognosticating disease progression or in predicting treatment success? Can we contribute to and improve personalized patient care by reliably forecasting the efficacy of current and novel treatment options? We address these questions in collaboration with private sector and clinical research partners. In particular, we study the signaling hubs of cell death and survival processes in patient tumors, using both transcriptomic and proteomic data, to define the individual likelihood to respond to therapies. Importantly, we integrate our mathematical models into these pipelines, with a view towards establishing novel systems medicine solutions. Our prior work in colorectal cancer, melanoma and glioblastoma demonstrated that combining information on cellular signaling with clinico-pathological and individual patient data has the potential to significantly contribute to personalizing treatment decisions in the future.

Publications

Schröder P, Wagner A, Stöhr D, Rehm M, Ehlers W. - Data-driven simulation of metastatic processes within brain tissue. PAMM, 17, 221--222 (December 2017). doi: 10.1002/pamm.201710080.

Hantusch A, Das KK, García-Sáez AJ, Brunner T, Rehm M. - Bax retrotranslocation potentiates Bcl-xL's antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance. Cell Death Dis. 2018 Mar 22;9(4):430. doi: 10.1038/s41419-018-0464-6.

Crawford N, Salvucci M, Hellwig CT, Lincoln FA, Mooney RE, O'Connor CL, Prehn JH, Longley DB, Rehm M. - Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711. Cell Death & Differentiation, 2018. doi: 10.1038/s41418-018-0082-y .

Apweiler R, Beissbarth T, Berthold MR, Blüthgen N, Burmeister Y, Dammann O, Deutsch A, Feuerhake F, Franke A, Hasenauer J, Hoffmann S, Höfer T, Jansen PL, Kaderali L, Klingmüller U, Koch I, Kohlbacher O, Kuepfer L, Lammert F, Maier D, Pfeifer N, Radde N, Rehm M, Roeder I, Saez-Rodriguez J, Sax U, Schmeck B, Schuppert A, Seilheimer B, Theis FJ, Vera J, Wolkenhauer O. - Whither systems medicine? Exp Mol Med. 2018 Mar 2;50(3):e453. doi: 10.1038/emm.2017.290. Review.

Carberry S, D’Orsi B, Monsefi N, Salvucci M, Bacon O, Fay J, Rehm M, McNamara D, Kay EW, Prehn J MH. - The BAX/BAK-like protein BOK is a prognostic marker in colorectal cancer. Cell Death & Disease, 9, 125-- (2018). doi: 10.1038/s41419-017-0140-.

Galluzzi L, [...], Rehm M, [...], Kroemer G. - Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation volume 25, pages486–541 (2018) doi:10.1038/s41418-017-0012-4.

Vetma V, Rožanc J, Charles EM, Hellwig CT, Alexopoulos LG, Rehm M. - Examining the in-vitro efficacy of the IAP antagonist Birinapant as a single-agent or in combination with Dacarbazine to induce melanoma cell death
Oncol Res. 2017 Mar 23. doi: 10.3727/096504017X14897145996933.

Salvucci M, Würstle ML, Morgan C, Curry S, Cremona M, Lindner AU, Bacon O, Resler AJ, Murphy AC, O’Byrne R, Flanagan L, Dasgupta S, Rice N, Pilati C, Zink E, Schöller LM, Toomey S, Lawler M, Johnston PG, Wilson R, Camilleri-Broët S, Salto-Tellez M, McNamara DA, Kay EW, Laurent-Puig P, Van Schaeybroeck S, Hennessy BT, Longley DB, Rehm M*, Prehn JH*. - A stepwise integrated approach to personalized risk predictions in stage III colorectal cancer.
Clin Cancer Res. 2017 Mar 1;23(5):1200-1212. *joint senior authors

Hantusch A, Brunner T, Frickey T, Rehm M. - Bcl-2-Ome - A database and interactive web service for dissecting the Bcl-2 interactome.
Cell Death Differ. 2017 Jan;24(1):192.

Weyhenmeyer B, Noonan J, Würstle ML, Johnston G, Rehm M*, Murphy B*. - Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide.
Oncotarget. 2016 Sep 20;7(38):61295-61311. *joint senior authors

Jacob SF, Würstle ML, Rehm M. - An analysis of the truncated Bid- and ROS-dependent spatial propagation of mitochondrial permeabilization waves during apoptosis
J Biol Chem. 2016 Feb 26;291(9):4603-13.

Klionsky DJ, [...], Rehm M, [...], Zughaier SM. - Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Autophagy. 2016 Jan 2;12(1):1-222.

Zakaria Z, Tivnan A, Flanagan L, Murray DW, Salvucci M, Stringer BW, Day BW, Boyd AW, Kogel D, Rehm M, O’Brien DF, Byrne AT, Prehn JH. - Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein (IAP) antagonist Birinapant.
Br J Cancer. 2015 Dec 10. doi: 10.1038/bjc.2015.420.

Wang S, Xia P, Rehm M, Fan Z. – Autophagy and cell reprogramming.
Cell Mol Life Sci. 2015 May;72(9):1699-713

Ichim G, Lopez J, Ahmed S, Muthalagu N, Giampazolias E, Delgado ME, Parsons MJ, von de Kooij B, Bouchier-Hayes L, Chalmers AJ, Borst J, Oberst A, Rehm M, Murphy DJ, Tait SW. – Limited mitochondrial permeabilisation causes DNA-damage and genomic instability in the absence of cell death.
Mol Cell. 2015 Mar 5;57(5):860-72

Parsons MJ, Rehm M, Bouchier-Hayes L. – Imaging-based methods for assessing caspase activity in single cells.
Cold Spring Harb Protoc. 2015 Jan 5;2015(1):pdb.top070342

Rehm M, Parsons MJ, Bouchier-Hayes L. - Measuring Caspase Activity by Förster Resonance Energy Transfer.
Cold Spring Harb Protoc. 2015 Jan 5;2015(1):pdb.prot082560

Charles EM, Rehm M. – Key regulators of apoptosis execution as biomarker candidates in melanoma.
Mol Cell Oncol. 2014 Dec23;1:3, e964037

Würstle ML, Rehm M. - A systems biological analysis of apoptosome formation and apoptosis execution supports allosteric procaspase‑9 activation.
J Biol Chem. 2014 Sep 19;289(38):26277-89.

Würstle ML, Zink E, Prehn JH, Rehm M. - From Computational Modelling of the Intrinsic Apoptosis Pathway to a Systems-Based Analysis of Chemotherapy Resistance: Achievements, Perspectives and Challenges in Systems Medicine.
Cell Death Dis. 2014 May 29;5:e1258

Delgado ME, Dyck L, Laussmann MA, Rehm M. - Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways.
Cell Death Dis. 2014 Jan 23;5:e1011.

Passante E, Würstle ML, Hellwig CT, Leverkus M, Rehm M. - Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells.
Cell Death Differ. 2013 Nov;20(11):1521-31.

Delgado ME, Olsson M, Lincoln FA, Zhivotovsky B, Rehm M. - Determining the contributions of caspase-2, caspase-8 and effector caspases to intracellular VDVADase activities during apoptosis initiation and execution.
Biochim Biophys Acta. 2013 Oct;1833(10):2279-92.

Murphy AC, Weyhenmeyer B, Schmid J, Rehm M, Huber HJ, Seifert V, Koegel D, Prehn JH, Murphy BM. - Activation of executioner caspases is a predictor of progression free survival in Glioblastoma Multiforme patients: a systems medicine approach.
Cell Death Dis. 2013 May 16;4:e629.

Rehm M, Prehn JH. - Systems modelling methodology for the analysis of apoptosis signal transduction and cell death decisions.
Methods. 2013 Jun 1;61(2):165-73.

Schmid J, Flanagan L, Lindner A, O'Connor CL, Rehm M, Prehn JH, Huber HJ. - Systems analysis of cancer heterogeneity in caspase-dependent apoptosis subsequent to mitochondrial outer membrane permeabilisation.
J Biol Chem. 2012 Nov 30;287(49):41546-59.

Würstle ML, Laussmann MA, Rehm M. - The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome.
Exp Cell Res. 2012 Jul 1;318(11):1213-20. Epub 2012 Feb 28 (Special Issue on Cell Death Signalling).

Hector S, Rehm M, Schmid J, Kehoe J, McCawley N, Dicker P, Murray F, McNamara D, Kay EW, Concannon CG, Huber HJ, Prehn JH. - Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy.
Gut. 2012 May;61(5):725-33. Epub 2011 Nov 14

Laussmann MA, Passante E, Hellwig CT, Tomiczek B, Flanagan L, Prehn JH, Huber HJ, Rehm M. - Proteasome inhibition can impair caspase-8 activation upon sub-maximal stimulation of apoptotic tumour necrosis factor-related apoptosis inducing ligand (TRAIL) signalling.
J Biol Chem. 2012 Apr 27;287(18):14402-11. Epub 2012 Mar 9

Hellwig CT, Rehm M. - TRAIL signalling and synergy mechanisms used in TRAIL-based combination therapies.
Mol Cancer Ther. 2012 Jan;11(1):3-13

Laussmann MA, Passante E, Dussmann H, Rauen JA, Würstle ML, Delgado ME, Devocelle M, Prehn JH, Rehm M. - Proteasome inhibition can induce an autophagy-dependent apical activation of caspase-8.
Cell Death Differ. 2011 Oct;18(10):1584-97

Ludwig-Galezowska AH, Flanagan L, Rehm M. - Apoptosis repressor with caspase recruitment domain, a multifunctional modulator of cell death.
J Cell Mol Med. 2011 May;15(5):1044-53

Flanagan L, Sebastia J, Delgado ME, Lennon JC, Rehm M. - Dimerisation of Smac is crucial for its mitochondrial retention by XIAP subsequent to mitochondrial outer membrane permeabilisation.
Biochim Biophys Acta. 2011 May;1813(5):819-26. Epub 2011 Feb 24

Huber HJ, Dussmann H, Kilbride S, Rehm M, Prehn JH. - Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.
Mol Syst Biol. 2011 Mar 1;7:470

Hellwig CT, Passante E, Rehm M. - The molecular machinery regulating apoptosis signal transduction and its implication in human physiology and pathophysiologies.
Curr Mol Med. 2011 Feb;11(1):31-47

Würstle ML, Laussmann MA, Rehm M. - The Caspase-8 Dimerisation/Dissociation Balance is a highly potent Regulator of the Caspase-8, -3, -6 Signalling Loop.
J Biol Chem. 2010 Oct 22;285(43):33209-18.

Flanagan L, Sebastià J, Tuffy LP, Spring A, Lichawska A, Devocelle M, Prehn JH, Rehm M. - XIAP impairs Smac Release from the Mitochondria during Apoptosis.
Cell Death Dis. 2010 Jun 6;1(1):e49

Hellwig CT, Ludwig-Galezowska AH, Concannon CG, Litchfield DW, Prehn JH, Rehm M. - Activity of Protein Kinase CK2 uncouples Bid Cleavage from Caspase-8 Activation.
J Cell Sci. 2010 May 1;123(Pt 9):1401-6.

Huber HJ, Laussmann MA, Prehn JH, Rehm M. - Diffusion is capable of translating anisotropic Apoptosis Initiation into a homogeneous Execution of Cell Death.
BMC Syst Biol. 2010 Feb 4;4(1):9.

Dussmann H, Rehm M, Concannon CG, Anguissola S, Wurstle M, Kacmar S, Voller P, Huber HJ, Prehn JH. - Single-Cell Quantification of Bax Activation and Mathematical Modeling Suggest Pore Formation upon Minimal Mitochondrial Bax Accumulation.
Cell Death Differ. 2010 Feb;17(2):278-90. Epub 2009 Sep 11

Wenus J, Dussmann H, Paul P, Kalamatianos D, Rehm M, Wellstead P, Prehn JH, Huber HJ. - ALISSA - An automated Live-Cell Imaging System for Signal-Transduction Analyses.
BioTechniques. 2009 Dec;47(6):1033-40.

Anguissola S, Köhler B, O’Byrne R, Düssmann H, Rehm M, Kögel D, Prehn JH. - Bid and Calpains cooperate to trigger Oxaliplatin-induced Apoptosis of Cervical Carcinoma HeLa Cells.
Mol Pharmacol. 2009 Nov;76(5):998-1010. Epub 2009 Aug 27

Rehm M*, Huber HJ, Hellwig CT, Anguissola S, Dussmann H, Prehn JH. – Dynamics of Outer Mitochondrial Membrane Permeabilization during Apoptosis
Cell Death Differ. 2009 Apr;16(4):613-23.

Farrelly AM, Wobser H, Bonner C, Anguissola S, Rehm M, Concannon CG, Prehn JH, Byrne MM. - Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-alpha (HNF1A) function in INS-1 insulinoma cells.
Diabetologia. 2009 Jan;52(1):136-44.

Huber HJ, Plchut M, Weisova P, Dussmann H, Rehm M, Ward MW, Prehn JH. - TOXI-SIM – A simulation tool for the analysis of mitochondrial and plasma membrane potentials.
J Neurosci Meth. 2009 Jan 30;176(2):270-5. Epub 2008 Sep 7,

Rudy A, López-Antón N, Barth N, Pettit GR, Dirsch VM, Schulze-Osthoff K, Rehm M, Prehn JH, Vogler M, Fulda S, Vollmar AM. - Role of Smac in cephalostatin-induced cell death.
Cell Death Differ. 2008 Dec;15(12):1930-40.

Köhler B, Anguissola S, Concannon CG, Rehm M, Kögel D, Prehn JH. - Bid participates in genotoxic drug-induced apoptosis of cervical cancer HeLa cells and is essential for the apoptotic and synergistic effects of death receptor ligands.
PLoS ONE. 2008 Jul 30;3(7):e2844.

O’Connor CL, Anguissola S, Huber HJ, Dussmann H, Prehn JH, Rehm M. - Intracellular signaling dynamics during apoptosis execution in presence or absence of X-linked-inhibitor-of-apoptosis-protein
Biochim Biophys Acta. 2008 Oct;1783(10):1903-13.

Hellwig CT, Kohler BF, Lehtivarjo A, Dussmann H, Courtney MJ, Prehn JH, Rehm M. - Real-time analysis of TRAIL/CHX-induced caspase activities during apoptosis initiation.
J Biol Chem. 2008 Aug 1;283(31):21676-85.

Huber HJ, Rehm M*, Plchut M, Dussmann H, Prehn JH. - APOPTO-CELL - a simulation tool and interactive database for analyzing cellular susceptibility to apoptosis
Bioinformatics. 2007 Mar 1;23(5):648-50

Konig HG, Rehm M, Gudorf D, Krajewski S, Reed JC, Gross A, Ward MW, Prehn JH. - Full Length Bid is Sufficient to Induce Apoptosis of Cultured Rat Hippocampal Neurons
BMC Cell Biol. 2007 Feb 27;8:7

Rehm M, Huber HJ, Dussmann H, Prehn JH. - Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein
EMBO J. 2006 Sep 20;25(18):4338-49

Ward MW, Rehm M, Dussmann H, Kacmar S, Concannon CG, Prehn JH. – Real time single cell analysis of Bid cleavage and Bid translocation during caspase-dependent and neuronal caspase-independent apoptosis
J Biol Chem. 2006 Mar 3;281(9):5837-44. Epub 2005 Dec 28

Rehm M, Dussmann H, Prehn JH. - Real-time single-cell analysis of Smac/DIABLO release during apoptosis
J Cell Biol. 2003 Sep 15;162(6):1031-43.

Dussmann H, Kogel D, Rehm M, Prehn JH. - Mitochondrial membrane permeabilization and superoxide production during apoptosis. A single-cell analysis.
J Biol Chem. 2003 Apr 11;278(15):12645-9.

Dussmann H, Rehm M, Kogel D, Prehn JH. - Outer mitochondrial membrane permeabilization during apoptosis triggers caspase-independent mitochondrial and caspase-dependent plasma membrane potential depolarization: a single-cell analysis.
J Cell Sci. 2003 Feb 1;116(Pt 3):525-36.

Rehm M, Dussmann H, Janicke RU, Tavare JM, Kogel D, Prehn JH. - Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process. Role of caspase-3.
J Biol Chem. 2002 Jul 5;277(27):24506-14.

Hellwig CT, Ludwig-Galezowska AH, Rehm M. – FRET-based measurement of apoptotic caspase activities by high-throughput screening flow cytometry.
Apoptosis Methods in Toxicology, in: Methods in Pharmacology and Toxicology Series, Springer Press. 2016 Editor-in-chief: Kang, Y. James; ISSN: 1557-2153. DOI 10.1007/978-01-4939-3588-8_7

Huber HJ, Bullinger E, Rehm M. - Systems biology approaches to the study of apoptosis
Essentials of Apoptosis, Humana Press, 2009, Nov; ISBN-13: 978-1603273800.

Huber HJ, Gomez Estrada G, Dussmann H, O’Connor C, Rehm M. - Extending the explanatory power of live cell imaging by computationally modelling the execution of apoptotic cell death
Modern Research and Educational Topics in Microscopy, Vol. 1; Formatex Microscopy Book Series, 2007 Jun, ISBN-13: 978-84-611-9419-3

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