Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer. (June 2014)

• Record Type: Journal Article
• Authors: Jaeger, Savina; Min, Junxia; Nigsch, Florian; Camargo, Miguel; Hutz, Janna; Cornett, Allen; Cleaver, Stephen; Buckler, Alan; Jenkins, Jeremy L.
• Is Part Of: Journal of biomolecular screening. Volume 19:Number 5(2014)
• Page Start: 791
• Page End: 802
• Publication Date: 2014-06
• Subjects: Causal modeling -- triple-negative breast cancer -- networks; Drugs -- Analysis -- Periodicals; Drugs -- Testing -- Periodicals; Biomolecules -- Analysis -- Periodicals; 572.36
• DOI: 10.1177/1087057114522690
• Languages: English
• ISSNs: 1087-0571

Abstract

Gene-expression data are often used to infer pathways regulating transcriptional responses. For example, differentially expressed genes (DEGs) induced by compound treatment can help characterize hits from phenotypic screens, either by correlation with known drug signatures or by pathway enrichment. Pathway enrichment is, however, typically computed with DEGs rather than "upstream" nodes that are potentially causal of "downstream" changes. Here, we present graph-based models to predict causal targets from compound-microarray data. We test several approaches to traversing network topology, and show that a consensus minimum-rank score (SigNet) beat individual methods and could highly rank compound targets among all network nodes. In addition, larger, less canonical networks outperformed linear canonical interactions. Importantly, pathway enrichment using causal nodes rather than DEGs recovers relevant pathways more often. To further validate our approach, we used integrated data sets from the Cancer Genome Atlas to identify driving pathways in triple-negative breast cancer. Critical pathways were uncovered, including the epidermal growth factor receptor 2–phosphatidylinositide 3-kinase–AKT–MAPK growth pathway and ATR –p53–BRCA DNA damage pathway, in addition to unexpected pathways, such as TGF–WNT cytoskeleton remodeling, IL12 -induced interferon gamma production, and TNFR–IAP (inhibitor of apoptosis) apoptosis; the latter was validated by pooled small hairpin RNA profiling in cancer cells. Overall, our approach can bridge transcriptional profiles to compound targets and driving pathways in cancer.