Abstract
Abstract Centrosome amplification is one of the most commonly observed abnormalities in human cancer and is associated with increased chromosome instability (CIN), aneuploidy and tumor progression. Cancer cells have been shown to cluster supernumerary centrosomes in a bipolar fashion in mitosis, thus preventing the formation of lethal multipolar spindles. We have developed isogenic cell lines, which enable us to identify genes which selectively kill tumor cells with centrosome amplification. The model is based on the generation of genomically stable human colon cancer DLD1 diploid and tetraploid (DLD1-T) cells with normal centrosome numbers and genomically unstable DLD1 intermediate (DLD1-I) with extra centrosomes generated by transiently blocking cytokinesis. Diploid and tetraploid populations did not show significant differences in gene expression, fitness, rate of spontaneous apoptosis, centrosome amplification and mitotic abnormalities. However, growth rate examination of the generated isogenic cell lines showed a slight increase in doubling time of DLD1-I clones, possibly due to a longer activation of the mitotic checkpoint machinery to allow time for microtubule attachment and centrosome clustering. To identify genes that their ablation leads to a selective cell killing of centrosome amplified cancer cells by centrosome declustering, we envisaged two parallel paths of investigation, an siRNA and a chemical library screening with a two-fold readout assay: a cell viability and a spindle morphology phenotypic assay by high-content microscopy. This approach allowed us to identify target genes and generate networks of genes that specifically kill cells with centrosome amplification by preventing centrosome clustering. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 889. doi:1538-7445.AM2012-889
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