title: Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape.
abstract: The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker-Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Anders
authors.initials: A
authors.lastname: Wennborg
authors.affiliation: Alba Nova University Center, Royal Institute of Technology, SE-10691 Stockholm, Sweden;
authors.forename: Erik
authors.initials: E
authors.lastname: Aurell
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Erez
authors.initials: E
authors.lastname: Dekel
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Jie-Zhi
authors.initials: JZ
authors.lastname: Zou
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205-2179;
authors.forename: Yuting
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Systems Biology, Seattle, WA 98109.
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; ingemar.ernberg@ki.se.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Ernberg
mesh_terms: D000465:Algorithms; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000235:genetics* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D034622:RNA Interference; D017455:Receptors, IgE / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D017455:Receptors, IgE; C491013:SLC22A2 protein, human; D018799:Intercellular Adhesion Molecule-1; D015260:Neprilysin
keywords: cancer cell attractor; cell heterogeneity; cell population dynamics; edge cells; gene regulatory network