Dysregulation of Cell Polarity Proteins Synergize with Oncogenes or the Microenvironment to Induce Invasive Behavior in Epithelial Cells

Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines

Social policy.

Contents: Part I: Theory. Some History Leading to Design Criteria for Bayesian Prediction; A.C. Atkinson, V.V. Fedorov. Optimal Designs for the Evaluation of an Extremum Point; R.C.H. Cheng, et al. On Regression Experiment Design in the Presence of Systematic Error; S.M. Ermakov. Gröbner Basis Methods in Mixture Experiments and Generalisations; B. Giglio, et al. Efficient Designs for Paired Comparisons with a Polynomial Factor; H. Großmann, et al. On Generating and Classifying All qn-m Regular Designs for Square-Free q; P.J. Laycock, P.J. Rowley. Second-Order Optimal Sequential Tests; M.B. Malyutov, I.I. Tsitovich. Variational Calculus in the Space of Measures and Optimal Design; I. Molchanov, S. Zuyev. On the Efficiency of Generally Balanced Designs Analysed by Restricted Maximum Likelihood; H. Monod. Concentration Sets, Elfving Sets and Norms in Optimum Design; A. Pázman. Sequential Construction of an Experimental Design from an I.I.D. Sequence of Experiments without Replacement; L. Pronzato. Optimal Characteristic Designs for Polynomial Models; J.M. Rodríguez-Díaz, J. López-Fidalgo. A Note on Optimal Bounded Designs; M. Sahm, R. Schwabe. Construction of Constrained Optimal Designs; B. Torsney, S. Mandal. Part II: Applications. Pharmaceutical Applications of a Multi-Stage Group Testing Method; B. Bond, et al. Block Designs for Comparison of Two Test Treatments with a Control; S.M. Bortnick, et al. Optimal Sampling Design with Random Size Clusters for a Mixed Model with Measurement Errors; A. Giovagnoli, L. Martino. Optimizing a Unimodal Response Function for Binary Variables; J. Hardwick, Q.F. Stout. An Optimizing Up-And-Down Design; E.E. Kpamegan, N. Flournoy. Further Results on Optimal and Efficient Designs for Constrained Mixture Experiments; R.J. Martin, et al. Coffee-House Designs; W.G. Müller. (D,t, C)-Optimal Run Orders; L. Tack, M. Vandebroek. Optimal Design in Flexible Models, including Feed-Forward Networks and Nonparametric Regression; D.M. Titterington. On Optimal Designs for High Dimensional Binary Regression Models; B. Torsney, N. Gunduz. Planning Herbicide Dose-Response Bioassays Using the Bootstrap; S.S. Zocchi, C.G. Borges Demétrio. Photo Gallery. Optimum Design 2000: List of Participants