Integrating Modelling of Metabolism and Signaling towards an Application in Liver Cancer

Summary
Uncontrolled proliferation in cancer results from synergistic adaptations in metabolism and signalling. However, due to the complexity, coupling mechanisms between metabolism and signalling are difficult to assess and it remains to be clarified how they give rise to cooperative enhancement. As a proof of concept, we focus on liver cancer, and propose a combined experimental and modelling approach that exploits both, comprehensive genome-scale models to identify global, cancer-specific alterations as well as a more detailed integrative model that links glycolysis and signalling. We will develop standard operating procedures for combined quantitative studies of metabolism and signal transduction in healthy and cancer cells, elucidate alterations in signalling and gene expression causing glycolytic adaptations and predict cancer-cell selective drug combinations using mathematical modelling of healthy and cancer cells. The proposed approach will act as a model study for systems biology approaches to integrate metabolism and signalling in oncology and will open new avenues for the treatment of liver cancer.

Project group
Ursula Klingmüller, German Cancer Research Center (DKFZ), Heidelberg, Germany
Jens Nielsen, Chalmers University of Technology, Sweden
Frank Bruggeman, VU University Amsterdam, the Netherlands
Daniel Seehofer, Charité University Medicine Berlin, Germany
Jens Timmer, University of Freiburg, Germany
Steven Tan, TTO VU University Amsterdam, the Netherlands
Iwan De Esch, Griffin Discoveries BV, the Netherlands