Data-Driven Modeling of Breast Cancer Tumors Using Boolean Networks.

Abstract

Cancer is a genomic disease involving various intertwined pathways with complex cross-communication links. Conceptually, this complex interconnected system forms a network, which allows one to model the dynamic behavior of the elements that characterize it to describe the entire system’s development in its various evolutionary stages of carcinogenesis. Knowing the activation or inhibition status of the genes that make up the network during its temporal evolution is necessary for the rational intervention on the critical factors for controlling the system’s dynamic evolution. In this report, we proposed a methodology for building data-driven boolean networks that model breast cancer tumors. We defined the network components and topology based on gene expression data from RNA-seq of breast cancer cell lines. We used a Boolean logic formalism to describe the network dynamics. The combination of single-cell RNA-seq and interactome data enabled us to study the dynamics of malignant subnetworks of up-regulated genes. First, we used the same Boolean function construction scheme for each network node, based on canalyzing functions. Using single-cell breast cancer datasets from The Cancer Genome Atlas, we applied a binarization algorithm. The binarized version of scRNA-seq data allowed identifying attractors specific to patients and critical genes related to each breast cancer subtype. The model proposed in this report may serve as a basis for a methodology to detect critical genes involved in malignant attractor stability, whose inhibition could have potential applications in cancer theranostics.