A 3D Multiscale Model to Explore the Role of EGFR Overexpression in Tumourigenesis

• Published in: Bulletin of mathematical biology Vol. 81; no. 7; pp. 2323 - 2344
• Main Authors: Bouchnita, Anass, Hellander, Stefan, Hellander, Andreas
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2019; Springer Nature B.V
• Subjects: Animals; Apoptosis; Biomechanical Phenomena; Brownian motion; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Biology; Cell division; Cell Proliferation; Cell surface; Computer Simulation; Deactivation; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Growth factors; Growth rate; Humans; Inactivation; Intracellular; Life Sciences; Mammalian cells; Mathematical and Computational Biology; Mathematical Concepts; Mathematical models; Mathematics; Mathematics and Statistics; Metabolic pathways; Models, Biological; Mutation; Nuclei (cytology); Object motion; Proteins; Raf protein; Receptors; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Software; Stochastic Processes; Stochasticity; Systems Analysis; Three dimensional models; Transcription factors; Tumorigenesis; Tumors; Up-Regulation; Agent-based modelling; EGFR; Brownian Dynamics; Tumour growth
• ISSN: 0092-8240; 1522-9602; 1522-9602
• DOI: 10.1007/s11538-019-00607-y

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.