title: Cellular network entropy as the energy potential in Waddington's differentiation landscape.
abstract: Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape.
authors.affiliation: 1] Statistical Cancer Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, United Kingdom [2] Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London WC1E6BT United Kingdom.
authors.forename: Christopher R S
authors.initials: CR
authors.lastname: Banerji
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
authors.forename: Simone
authors.initials: S
authors.lastname: Severini
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.forename: Joseph X
authors.initials: JX
authors.lastname: Zhou
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
mesh_terms: D000465:Algorithms; D002454:Cell Differentiation; D019070:Cell Lineage; D002468:Cell Physiological Phenomena; D019277:Entropy; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology