title: Using Cell Culture Models of Centrosome Amplification to Study Centrosome Clustering in Cancer.
abstract: The link between centrosome amplification and cancer has been recognized for more than a century, raising many key questions about the biology of both normal and cancer cells. In particular, the presence of extra centrosomes imposes a great challenge to a dividing cell by increasing the likelihood of catastrophic multipolar divisions. Only recently have we begun to understand how cancer cells successfully divide by clustering their extra centrosomes for bipolar division. Several hurdles to dissecting centrosome clustering include limitations in the methodologies used to quantify centrosome amplification, and the lack of appropriate cell culture models. Here, we describe how to accurately assess centrosome number and create isogenic cell lines with or without centrosome amplification. We then describe how imaging of cell division in these cell culture models leads to identification of the molecular machinery uniquely required for cells with extra centrosomes. These approaches have led to the identification of molecular targets for selective cancer therapeutics that can kill cancer cells with extra centrosomes without affecting normal cells with two centrosomes. We further anticipate that the approaches described here will be broadly applicable for studying the causes and consequences of centrosome amplification in a variety of contexts across cancer pathophysiology, such as cell migration and metastasis.
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. mijung_kwon@dfci.harvard.edu.|Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. mijung_kwon@dfci.harvard.edu.
authors.forename: Mijung
authors.initials: M
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018385:Centrosome / Q000378:metabolism*; D048749:Cytokinesis / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D008941:Spindle Apparatus / Q000378:metabolism; D057891:Tetraploidy
chemical_list: C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Aneuploidy; Cancer; Cell division; Centrosome; Centrosome amplification; Extra centrosomes; Mitosis; Multipolar spindle; Selective cancer therapeutics