GENAVOS: A New Tool for Modelling and Analyzing Cancer Gene Regulatory Networks Using Delayed Nonlinear Variable Order Fractional System

Abstract

Gene regulatory networks (GRN) are one of the etiologies associated with cancer. Their dysregulation can be associated with cancer formation and asymmetric cellular functions in cancer stem cells, leading to disease persistence and resistance to treatment. Systems that model the complex dynamics of these networks along with adapting to partially known real omics data are closer to reality and may be useful to understand the mechanisms underlying neoplastic phenomena. In this paper, for the first time, modelling of GRNs is performed using delayed nonlinear variable order fractional (VOF) systems in the state space by a new tool called GENAVOS. Although the tool uses gene expression time series data to identify and optimize system parameters, it also models possible epigenetic signals, and the results show that the nonlinear VOF systems have very good flexibility in adapting to real data. We found that GRNs in cancer cells actually have a larger delay parameter than in normal cells. It is also possible to create weak chaotic, periodic, and quasi-periodic oscillations by changing the parameters. Chaos can be associated with the onset of cancer. Our findings indicate a profound effect of time-varying orders on these networks, which may be related to a type of cellular epigenetic memory. By changing the delay parameter and the variable order functions (possible epigenetics signals) for a normal cell system, its behaviour becomes quite similar to the behaviour of a cancer cell. This work confirms the effective role of the miR-17-92 cluster as an epigenetic factor in the cancer cell cycle.

Keywords

• gene regulatory networks
• non-linear variable order fractional system
• gene expression
• epigenetic memory