Research

Investigators > Markus RehmResearch, please also see Team Members

Research Interests

My team addresses systemsbiological and systemsmedical research questions in highly therapy-resistant cancers. We are particularly interested in the molecular and systems-level understanding of apoptosis signal transduction in response to death ligands, proteasome inhibitors, and genotoxic drugs, and how apoptosis signalling interacts with and is modulated by non-apoptotic signalling processes. To this end, we develop novel experimental and mathematical research tools that allow to investigate cell fate decision processes quantitatively at the single cell level (cervical, colorectal and breast cancer cell line models, as well as biologically highly heterogeneous malignant melanoma cell line models). Our research findings and newly developed methods feed into translational research projects and collaborations that are geared towards introducing systems biology into the clinical research arena.

1. Systems Biology of Cell Death and Survival Decisions
A comprehensive and functional understanding of complex signalling networks with multiple parallel variables can only be obtained on the systems level. My team combines quantitative cell biological, biophysical and biophotonic analyses with mathematical models into new systems biological approaches to describe and analyse intracellular signalling dynamics controlling cell fate decisions between death and survival. This approach yielded experimental systems studies that allowed a quantitative one-to-one comparison of mathematical predictions and experimentally measured death signalling responses of individual cells. We accurately predicted signalling kinetics, identified critical threshold concentrations of regulator proteins as well as a molecular switch mechanism deciding on cell death. By now, modelling strategies have been successfully expanded from temporal kinetic modelling to include spatial reaction-diffusion modelling as well as knowledge- and data-driven statistical modelling. In collaborative work with RCSI researchers within the department and beyond we conduct translational research studies, in which we apply predictive systems models in a clinical context. We furthermore develop novel screening strategies to understand drug and dual-drug (inter)actions by high throughput flow cytometry and coupled mathematical response analysis.

2. Cell Biology of Programmed Cell Death
Excessive or reduced cell death are a frequent cause of degenerative and proliferative diseases in multicellular organisms: Deregulated cell death signalling, amongst others, has been implicated in autoimmunity, cancers and neoplasms as well as in neurological pathophysiologies. My team employs quantitative cell biological, biochemical, cytometric and microscopic techniques to investigate human cells to unravel control features in the signal transduction networks of apoptosis. Central apoptotic signalling events are controlled by the complex interplay of multiple proteins, and by multi-protein complexes that form in cell membranes. Knowledge on the assembly and signal transduction kinetics and their modulation and regulation is required to understand hiw these signalling processes control cellular decisions between life and death. Cells with specific deficits in theses signalling networks allow us to experimentally obtain quantitative insight into drug resistance mechanisms, both in response to widely used chemotherapeutics as well as promising novel compounds.

3. Biophotonic Single Cell and High-throughput Analysis
Biophotonic methodology has become one of the most challenging and important experimental fields in cell biological, biomedical and pharmacological research in the genomic and postgenomic era. The analysis of individual cells by cytometry or time-lapse microscopy based on absorbance, fluorescence and light scattering allows deep insight into intracellular protein dynamics, interactions and activities, as well as into ion concentrations, electrochemical membrane potentials any many other cellular processes and characteristics. These measurements allow the real time analysis of intracellular processes and their functional consequences in the natural environment: within the complexity of the living cell. We have established the combination of multi-parametric imaging, multi-channel cytometry and complex computer-assisted data analysis as a foundation of our basic experimental systems biology research strategies, and develop these technologies further as part of translational, clinical research projects.

Funding history 

APO-DECIDE Consortium – Apoptosis Modelling for Treatment Decisions in Colorectal Cancer 2012
FP7-HEALTH-2012-INNOVATION-1
Collaborator – 1.5 postdoctoral positions
Partners involved: Prehn J, RCSI, Ireland; Gallagher W, Oncomark Ltd, Ireland; Johnston P, Queens University, UK; Laurent-Puig P, Paris Descartes University, France; Kleiman M, Optimata Ltd, Israel; Clissman C, Pintail Ltd, Ireland; Fulda S, University Hospital Frankfurt, Germany.
Nov 2012 – Oct 2014

Flynn SO, Rehm M. – Quantitative systems analysis of the apoptotic signalling network in human neuroblastoma
Merck Sharp & Dohme Award in Cancer 2011

Rehm M. Intracellular caspase activation profiles in response to chemotherapeutic drugs: role of caspase-2
Science Foundation Ireland: Research Frontiers Program 2009
October 2009 – September 2013

Ludwig-Galezowska A. & Rehm M. – Establishing Biophotonic Workflows for High-Throughput Cytometry and 3D Time-Lapse Imaging to investigate Cancer Cell Resistance to Apoptosis
NBIPI/FP7 Marie Curie CEMP Programme 2009
September 2009 – August 2011

Rehm M. – Computational systems biology of apoptosis signalling
HEA/PRTLI – National Biophotonics and Imaging Platform PhD studentship
September 2008 – August 2012

Rehm M. A comprehensive systems approach to evaluate PAC-1 based strategies for sensitizing malignant melanoma to apoptotic cell death
Health Research Board: Research Project Grant
October 2008 – March 2012

Rehm M. The synergistic potential of novel chemotherapeutic drugs in inducing apoptotic cell death in highly resistant human colon cancer cells
Science Foundation Ireland: STAR program
June 2007 – August 2007

Rehm M. Real-time detection of Caspases-8/-10 Activity at the Interface between Apoptosis Initiation and Execution
Science Foundation Ireland: Research Frontiers Program 2007
May 2007 – April 2010

Rehm M. A qualitative and quantitative evaluation of PAC-1-like compounds as a novel treatment paradigm for highly resistant cancer cells.
Royal College of Surgeons Research Committee Grant
May 2007 – April 2010

Rehm M. Targeting the Cell Death Resistance of Cervical Cancer Cells: A qualitative and quantitative evaluation of Smac/Smac-like Peptides and Proteasome Inhibitors in the treatment of cancer.
Health Research Board: Research Project Grant
October 2006 – September 2009

Rehm M. Equipment for general project grants 2005/2006
Health Research Board: Supplementary equipment funding
August 2006

Rehm M. Mitochondrial permeabilisation during apoptotic cell death in response to novel chemotherapeutic agents
Science Foundation Ireland: UREKA site project
July – August 2006

Rehm M. The potency of Inhibitor of Apoptosis Proteins (IAPs) in controlling death receptor mediated apoptosis of type I cells
Science Foundation Ireland: SPUR program
July – August 2006

Rehm M. Activation of programmed cell death (apoptosis) signaling in highly resistant human cancer cells
Science Foundation Ireland: STAR program
June 2006 – August 2006

Rehm M.  Inhibitor-of-Apoptosis-Proteins in cancer therapy and tumor progression: A molecular analysis.
Science Foundation Ireland: Research Frontiers Program 2005
August 2005 – August 2008

 

Additional collaborative Projects and Consortia:

National Biophotonics and Imaging Platform – Equipment Applications 2008: Flow Cytometric High Throughput Platform (Lead-PI; joint proposal with Moran N, Harvey B, Prehn J, O’Neill S, Harmey J)

Project Collaborator: APO-SYS Consortium – Apoptosis Systems Biology applied to Cancer and AIDS
FP7 HEALTH 2007 A
http://www.apo-sys.eu/

Irish National Biophotonics and Imaging Platform (NBIP)
Irish HEA, PRTLI Cycle 4, National Collaborative Programme 2008

Project Collaborator: APOCOLON: Qualitative and quantitative analysis of factors contributing to apoptosis resistance in colorectal cancer: Evaluation of new prognostic and therapeutic avenues
Led by Prof. Jochen Prehn and Prof. Elaine Kay, RCSI
Health Research Board; Translational Research Grant 2007

High content live cell imaging platform
Together with Prof. J Prehn (Lead-PI), Dr. D Henshall (co-PI), Dr. H Huber (co-PI)
Science Foundation Ireland, Equipment Call 2007

Additional equipment for general project grants 2005/2006 (co-PI; joint proposal with Henshall D, Prehn J, Treumann A)
Health Research Board: Funding for an Ultra-Centrifuge
September 2006