Normalizing Input–Output Relationships of Cancer Networks for Reversion Therapy

Accumulated genetic alterations in cancer cells distort cellular stimulus‐response (or input–output) relationships, resulting in uncontrolled proliferation. However, the complex molecular interaction network within a cell implicates a possibility of restoring such distorted input–output relationships by rewiring the signal flow through controlling hidden molecular switches. Here, a system framework of analyzing cellular input–output relationships in consideration of various genetic alterations and identifying possible molecular switches that can normalize the distorted relationships based on Boolean network modeling and dynamics analysis is presented. Such reversion is demonstrated by the analysis of a number of cancer molecular networks together with a focused case study on bladder cancer with in vitro experiments and patient survival data analysis. The origin of reversibility from an evolutionary point of view based on the redundancy and robustness intrinsically embedded in complex molecular regulatory networks is further discussed.