The year 2012 started well for the Centre of Systems Medicine by providing two new studies that extend the Centre of Systems Medicine’s competency in methodological approaches and address, for the first time in the history of the centre and the department, two respected journals in the field of Theoretical and Systems Biology.
A study by Heinrich Huber (corresponding author), Niamh Connolly, Heiko Dussmann and Jochen H. M. Prehn was released online in the journal Molecular BioSystems on January 5th. The paper provided a novel approach that addresses the gap between mechanistically detailed ODE models (which are often impractical for studying large systems because of their highly detailed nature) and models using top-down control analysis (which allow to identify abstract regulation principles, but are not mechanistically justified and often only practicable for systems close to steady state). The new approach will come handy when larger systems are studied that combine metabolic processes (often quasi-steady state processes) with oncogenic signalling (heavily dynamic).
A second paper by Fernando Lopez-Caamal, Miriam Garcia, Rick Middleton and Heinrich Huber was accepted in the Journal of Theoretical Biology on January 13th. The paper is a result of a collaboration between the National University of Maynooth and the Centre of Systems Medicine, RCSI, within the mathematical modelling core of the National Biophotonics Platform (NBIP). Using a pure mathematical treatment, the authors investigated how growth signals in skeletal muscle cells are propagating in space and time. Since such partial differential equations are often hard or impossible to solve, the authors came up with two biologically justified approximations that allow mathematically exact solutions. Using Fourier Analysis, they demonstrated that a signal auto-feedback and diffusion act as a low-pass filter to eliminate fluctuations in signal input. The theoretically predicted filter may be a prototypical motif for signal propagation in larger cells.
On behalf of RCSI and Prof. Jochen Prehn, you are cordially invited to the launch of the
Centre for Systems Medicine
Albert Lecture Theatre, Royal College of Surgeons in Ireland,
123 St. Stephens Green
Wednesday January 11th 2012 9.30-11.30 am
The mission statement of the Centre for Systems Medicine, RCSI is to provide a translational research centre which identifies proteins implicated in human disease and utilizes systems biology and mathematical approaches in order to develop new prognostic tools for the treatment of cancer, neurological disorders and diabetes, and to develop more targeted therapies for patients.
The Centre for Systems Medicine is generously supported through funding from national and international funding bodies, including Science Foundation Ireland, Health Research Board, National Biophotonics Imaging Platform Ireland, European Commission Seventh Framework Programme 7, Higher Education Authority and Enterprise Ireland.
TFAP2E gene hypermethylation associated with clinical non-responsiveness to chemotherapy in colorectal cancer
In many cancers different patterns of DNA methylation (epigenetics) appear likely to discriminate aggressive versus nonaggressive disease and to predict responsiveness to specific treatments.
A new study led by Prof Matthias Ebert and Dr Marc Taenzer (University Hospital Mannheim and Technical University, Munich, Germany) and collaborators based in Germany and Dr David Hughes at the Centre for Systems Medicine in the RCSI has found that an epigenetic change common in colorectal cancer predicts poor response to chemotherapy.
The study published in the January 5th 2012 edition of the New England Journal of Medicine* shows that TFAP2E gene hypermethylation (i.e., highly methylated gene sequences) was associated with clinical non-responsiveness to chemotherapy in colorectal cancer.
The researchers collected samples from patients undergoing surgery or chemotherapy for colorectal cancer at six German university hospitals. In the initial cohort of 74 patients whose tumour DNA was analyzed, 38 showed TFAP2E hypermethylation (51%), which didn’t correlate with tumor site, grade, stage, or any other common clinical or pathological characteristics. In four cohorts totalling 220 colorectal patients treated with fluorouracil-based chemotherapy or chemoradiation through different clinical trials TFAP2E epigenetic alteration was associated with significantly lower tumour response rates.
*Ebert MPA, Taenzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ, Tetzner R, Lofton-Day C, Rosenberg R, Reinacher-Schick A, Schulmann K, Hofheinz R, Roecken C, Keller G, Langer R, Stoehlmacher J, Schuster T, Stroebel P, Schmid R (2012) TFAP2E/DKK4 and Chemoresistance in Colorectal Cancer. New England Journal of Medicine, 366, 44-53.