Modeling community-wide molecular networks of multicellular systems.

Abstract

Multicellular systems, such as tissues, are composed of different cell types that form a heterogeneous community. Behavior of these systems is determined by complex regulatory networks within (intracellular networks) and between (intercellular networks) cells. Increasingly more studies are applying genome-wide experimental approaches to delineate the contributions of individual cell types (e.g. stromal, epithelial, vascular cells) to collective behavior of heterogeneous cell communities (e.g. tumors). Although many computational methods have been developed for analyses of intracellular networks based on genome-scale data, these efforts have not been extended toward analyzing genomic data from heterogeneous cell communities. Here, we propose a network-based approach for analyses of genome-scale data from multiple cell types to extract community-wide molecular networks comprised of intra- and intercellular interactions. Intercellular interactions in this model can be physical interactions between proteins or indirect interactions mediated by secreted metabolites of neighboring cells. Applying this method on data from a recent study on xenograft mouse models of human lung adenocarcinoma, we uncover an extensive network of intra- and intercellular interactions involved in the acquired resistance to angiogenesis inhibitors. Supplementary data are available at Bioinformatics online.