title: Elucidation of epithelial-mesenchymal transition-related pathways in a triple-negative breast cancer cell line model by multi-omics interactome analysis.
abstract: In life sciences, and particularly biomedical research, linking aberrant pathways exhibiting phenotype-specific alterations to the underlying physical condition or disease is an ongoing challenge. Computationally, a key approach for pathway identification is data enrichment, combined with generation of biological networks. This allows identification of intrinsic patterns in the data and their linkage to a specific context such as cellular compartments, diseases or functions. Identification of aberrant pathways by traditional approaches is often limited to biological networks based on either gene expression, protein expression or post-translational modifications. To overcome single omics analysis, we developed a set of computational methods that allow a combined analysis of data collections from multiple omics fields utilizing hybrid interactome networks. We apply these methods to data obtained from a triple-negative breast cancer cell line model, combining data sets of gene and protein expression as well as protein phosphorylation. We focus on alterations associated with the phenotypical differences arising from epithelial-mesenchymal transition in two breast cancer cell lines exhibiting epithelial-like and mesenchymal-like morphology, respectively. Here we identified altered protein signaling activity in a complex biologically relevant network, related to focal adhesion and migration of breast cancer cells. We found dysregulated functional network modules revealing altered phosphorylation-dependent activity in concordance with the phenotypic traits and migrating potential of the tested model. In addition, we identified Ser267 on zyxin, a protein coupled to actin filament polymerization, as a potential in vivo phosphorylation target of cyclin-dependent kinase 1.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark. jkp@bmb.sdu.dk.
authors.forename: Josch K
authors.initials: JK
authors.lastname: Pauling
authors.forename: Anne G
authors.initials: AG
authors.lastname: Christensen
authors.forename: Richa
authors.initials: R
authors.lastname: Batra
authors.forename: Nicolas
authors.initials: N
authors.lastname: Alcaraz
authors.forename: Eudes
authors.initials: E
authors.lastname: Barbosa
authors.forename: Martin R
authors.initials: MR
authors.lastname: Larsen
authors.forename: Hans C
authors.initials: HC
authors.lastname: Beck
authors.forename: Rikke
authors.initials: R
authors.lastname: Leth-Larsen
authors.forename: Vasco
authors.initials: V
authors.lastname: Azevedo
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.forename: Jan
authors.initials: J
authors.lastname: Baumbach
mesh_terms: D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D010766:Phosphorylation / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*