Abstract
The epidermal growth factor receptor (EGFR) signalling cascade is one of the main pathways that regulate the survival and division of mammalian cells. It is also one of the most altered transduction pathways in cancer. Acquired mutations in the EGFR/ERK pathway can cause the overexpression of EGFR on the surface of the cell, while others downregulate the inactivation of switched on intracellular proteins such as Ras and Raf. This upregulates the activity of ERK and promotes cell division. We develop a 3D multiscale model to explore the role of EGFR overexpression on tumour initiation. In this model, cells are described as individual objects that move, interact, divide, proliferate, and die by apoptosis. We use Brownian Dynamics to describe the extracellular and intracellular regulations of cells as well as the spatial and stochastic effects influencing them. The fate of each cell depends on the number of active transcription factors in the nucleus. We use numerical simulations to investigate the individual and combined effects of mutations on the intracellular regulation of individual cells. Next, we show that the distance between active receptors increase the level of EGFR/ERK signalling. We demonstrate the usefulness of the model by quantifying the impact of mutational alterations in the EGFR/ERK pathway on the growth rate of in silico tumours.
Highlights
The epidermal growth factor receptor (EGFR)/ERK cascade is one of the main mitogen activated-protein kinase (MAPK) pathways that regulate the survival and division of several mammalian cells (Orton et al 2005)
We develop a multiscale model capable of describing the effects of mutational changes in the EGFR/ERK pathway on tumour initiation
In order to describe this signalling process under normal conditions and in cancer, we develop a novel model that integrates three modules for each of the underlying processes: ligand–receptor interactions (Sect. 2.1), intracellular regulation (Sect. 2.2), and multicellular biomechanics (Sect. 2.3) (Fig. 1)
Summary
The EGFR/ERK cascade is one of the main mitogen activated-protein kinase (MAPK) pathways that regulate the survival and division of several mammalian cells (Orton et al 2005). This signalling cascade is stimulated when epidermal growth factors (EGFs) bind to their receptors (EGFRs) present on the membrane surface of cells. The diffusing RasGTPs subsequently interact with Raf which, upon activation, dually phosphorylate and activate MEK proteins. MEKs participate in the formation of active ERKs. ERK proteins phosphorylates RSK and both of them translocate to the nucleus where they activate several transcription factors such as CREB, Fos, and Elk-1
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