Nature Communications 8, Article number: 198 (2017)

Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures.

Khan FM, Marquardt S, Gupta SK, Knoll S, Schmitz U, Spitschak A, Engelmann D, Vera J, Wolkenhauer O, Pützer BM.

Abstract


Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial–mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.