‘A systems biology approach towards understanding signal trasnsduction regulatory networks controlling cell division and cancer’

Boris N. Kholodenko, David A. Fell, Francesc Mas, Hans Victor Westerhoff, Josep Joan Centelles, Marta Cascante Serratosa, Neus Agell.

The pathway initiated by Epidermal Growth Factor (EGF) and related signals binding to members of the family of EGF receptors is involved in a number of human squamous cell cancers. This has led to drug development programmes targeting various components of the EGF pathway.It is nevertheless the case that the response of cancers to these drug candidates has often not been as expected. This shows that our understanding of these pathways and of their involvement in cancer cell proliferation is insufficient for predictive purposes.

The key aims of this project are therefore to develop an improved simulation of growth factor signalling that models the responses of cells over a longer time scale and can be adapted to represent different cancer cell types and their responses to growth factors and drugs. This will require: 1) Updating existing models to represent the events around ligand-receptor interaction and activation of receptor tyrosine kinase in more detail, and to take account of the interactions between the different receptor types (EGFR, HER family etc.) present in various cancers. 2) Extension of the models to simulate events over a longer period following growth factor stimulation. 3) Validation of the model by comparison with experiments on standard cell lines, involving responses to growth factor stimulation in the presence and absence of various drugs and inhibitors. 4) Determination of the levels and activities of the signalling molecules in a range of cancer cell lines that are growth-factor dependent, so that the model can be modified to represent these different cancer types. 5) Testing the predictions of these ?tuned? models relative to the response of the cancer cell lines to drug inhibition.