Global stabilization of Boolean networks to control the heterogeneity of cellular responses

Abstract

Boolean networks (BNs) have been widely used as a useful model for molecular regulatory networks in systems biology. In the state space of BNs, attractors represent particular cell phenotypes. For targeted therapy of cancer, there is a pressing need to control the heterogeneity of cellular responses to the targeted drug by reducing the number of attractors associated with the ill phenotypes of cancer cells. Here, we present a novel control scheme for global stabilization of BNs to a unique fixed point. Using a sufficient condition of global stabilization with respect to the adjacency matrix, we can determine a set of constant controls so that the controlled BN is steered toward an unspecified fixed point which can then be further transformed to a desired attractor by subsequent control. Our method is efficient in that it has polynomial complexity with respect to the number of state variables, while having exponential complexity with respect to in-degree of BNs. To demonstrate the applicability of the proposed control scheme, we conduct simulation studies using a regulation influence network describing the metastatic process of cells and the Mitogen-activated protein kinase (MAPK) signaling network that is crucial in cancer cell fate determination.