Investigating Mechanisms of Robust Perfect Adaptation in Cancer Metabolisms Using Chemical Reaction Network Theory

Abstract

Perfect adaptation is a ubiquitous phenomenon in biology, characterized by the ability of living cells to maintain chemical levels despite disturbances. This adaptation is said to be robust when it holds even after parameter variations. This property of the system is called Robust Perfect Adaptation (RPA). When certain variables lose this property or undesired chemical species acquire RPA property, it results in disease conditions. Metabolic adaptation in extreme tumor microenvironment is a hallmark of cancer cells and allows them to evade death and develop drug resistance. Hence, it is important to investigate the robustness properties of cancer metabolism using a system-theoretical approach. In this work, we topologically investigate the robust perfect adaptation property of large-scale metabolic reaction networks of three types of cancers using the theory proposed by Hirono, Gupta, and Khammash, 2023 (https://arxiv.org/abs/2307.07444). We enumerate the RPA properties of all biologically relevant reactions in large-scale metabolic models of cancer cells, along with the corresponding healthy cells. Finally, perform a comparative analysis to identify drug targets based on the differences in the RPA properties between healthy and cancer cell metabolisms.