title: Systematic drug perturbations on cancer cells reveal diverse exit paths from proliferative state.
abstract: During a cell state transition, cells travel along trajectories in a gene expression state space. This dynamical systems framework complements the traditional concept of molecular pathways that drive cell phenotype switching. To expose the structure that hinders cancer cells from exiting robust proliferative state, we assessed the perturbation capacity of a drug library and identified 16 non-cytotoxic compounds that stimulate MCF7 breast cancer cells to exit from proliferative state to differentiated state. The transcriptome trajectories triggered by these drugs diverged, then converged. Chemical structures and drug targets of these compounds overlapped minimally. However, a network analysis of targeted pathways identified a core signaling pathway--indicating common stress-response and down-regulation of STAT1 before differentiation. This multi-trajectory analysis explores the cells' state transition with a multitude of perturbations in combination with traditional pathway analysis, leading to an encompassing picture of the dynamics of a therapeutically desired cell-state switching.
authors.affiliation: Institute for Systems Biology, Seattle WA, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta, Canada.
authors.forename: Joseph X
authors.initials: JX
authors.lastname: Zhou
authors.affiliation: Computer Engineering Department, Dokuz Eylul University, Izmir, Turkey.|Biotechnology Center, TU Dresden, Dresden, Germany.
authors.forename: Zerrin
authors.initials: Z
authors.lastname: Isik
authors.affiliation: Institute for Biocomplexity and Informatics, University of Calgary, Alberta, Canada.
authors.forename: Caide
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Institute for Systems Biology, Seattle WA, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Rubin
authors.affiliation: Institute for Systems Biology, Seattle WA, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta, Canada.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Kauffman
authors.affiliation: Biotechnology Center, TU Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeder
authors.affiliation: Institute for Systems Biology, Seattle WA, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta, Canada.
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019295:Computational Biology / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents
keywords: cancer cell differentiation; cancer drug screen; cell state transition; dynamical system; gene regulatory network