Data-driven structural analysis of small cell lung cancer transcription factor network suggests potential subtype regulators and transition pathways

Small cell lung cancer (SCLC) is an aggressive disease and challenging to treat due to its mixture of transcriptional subtypes and subtype transitions. Transcription factor (TF) networks have been the focus of studies to identify SCLC subtype regulators via systems approaches. Yet, their structures, which can provide clues on subtype drivers and transitions, are barely investigated. Here, we analyze the structure of an SCLC TF network by using graph theory concepts and identify its structurally important components responsible for complex signal processing, called hubs. We show that the hubs of the network are regulators of different SCLC subtypes by analyzing first the unbiased network structure and then integrating RNA-seq data as weights assigned to each interaction. Data-driven analysis emphasizes MYC as a hub, consistent with recent reports. Furthermore, we hypothesize that the pathways connecting functionally distinct hubs may control subtype transitions and test this hypothesis via network simulations on a candidate pathway and observe subtype transition. Overall, structural analyses of complex networks can identify their functionally important components and pathways driving the network dynamics. Such analyses can be an initial step for generating hypotheses and can guide the discovery of target pathways whose perturbation may change the network dynamics phenotypically.