Examining the link between chromosomal instability and aneuploidy in human cells
TLDR
It is shown that improper microtubule–chromosome attachment (merotely) is a cause of chromosome missegregation in unstable cells and that increasing chromosome misSEgregation rates by elevating merotely during consecutive mitoses generates CIN in otherwise stable, near-diploid cells.Abstract:
Solid tumors can be highly aneuploid and many display high rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). In principle, aneuploidy is the consequence of CIN, but the relationship between CIN and aneuploidy has not been clearly defined. In this study, we use live cell imaging and clonal cell analyses to evaluate the fidelity of chromosome segregation in chromosomally stable and unstable human cells. We show that improper microtubule–chromosome attachment (merotely) is a cause of chromosome missegregation in unstable cells and that increasing chromosome missegregation rates by elevating merotely during consecutive mitoses generates CIN in otherwise stable, near-diploid cells. However, chromosome missegregation compromises the proliferation of diploid cells, indicating that phenotypic changes that permit the propagation of nondiploid cells must combine with elevated chromosome missegregation rates to generate aneuploid cells with CIN.read more
Citations
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The causes and consequences of genetic heterogeneity in cancer evolution.
TL;DR: Insight is gained into the common pathways of tumour evolution that could support the development of future therapeutic strategies and shape the evolution of the cancer genome through a plethora of mechanisms.
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A Mechanism Linking Extra Centrosomes to Chromosomal Instability
TL;DR: It is demonstrated that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable, and it is proposed that this mechanism may be a common underlying cause of CIN in human cancer.
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Chromosomal instability drives metastasis through a cytosolic DNA response.
Samuel F. Bakhoum,Samuel F. Bakhoum,Bryan Ngo,Ashley M. Laughney,Julie Ann Cavallo,Julie Ann Cavallo,Charles J. Murphy,Peter Ly,Pragya Shah,Roshan K. Sriram,Thomas B.K. Watkins,Neil K. Taunk,Mercedes Duran,Mercedes Duran,Chantal Pauli,Christine Shaw,Kalyani Chadalavada,Vinagolu K. Rajasekhar,Giulio Genovese,Subramanian Venkatesan,Nicolai Juul Birkbak,Nicholas McGranahan,Mark R. Lundquist,Quincey LaPlant,John H. Healey,Olivier Elemento,Christine H. Chung,Nancy Y. Lee,Marcin Imielenski,Gouri Nanjangud,Dana Pe'er,Don W. Cleveland,Simon N. Powell,Jan Lammerding,Charles Swanton,Lewis C. Cantley +35 more
TL;DR: It is shown that chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs by sustaining a tumour cell-autonomous response to cytosolic DNA.
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Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis
TL;DR: The mitotic checkpoint is a major cell cycle control mechanism that guards against chromosome missegregation and the subsequent production of aneuploid daughter cells.
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Cancer Cells Display Profound Intra- and Interline Variation following Prolonged Exposure to Antimitotic Drugs
TL;DR: An automated time-lapse light microscopy approach is used to systematically analyze over 10,000 single cells from 15 cell lines in response to three different classes of antimitotic drug, showing that the variation in cell behavior is far greater than previously recognized.
References
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Journal ArticleDOI
Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Journal ArticleDOI
Genetic instability in colorectal cancers
TL;DR: It is shown that colorectal tumours without microsatellite instability exhibit a striking defect in chromosome segregation, resulting in gains or losses in excess of 10 –2 per chromosome per generation, and that such instability can arise through two distinct pathways.
Journal ArticleDOI
Mutations of mitotic checkpoint genes in human cancers
Daniel P. Cahill,Christoph Lengauer,Jian Yu,Gregory J. Riggins,James K V Willson,Sanford D. Markowitz,Kenneth W. Kinzler,Bert Vogelstein +7 more
TL;DR: It is shown that CIN is consistently associated with the loss of function of a mitotic checkpoint in cancers displaying CIN, and in some cancersThe loss of this checkpoint wasassociated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB 1 controls mitotic checkpoints and chromosome segregation in yeast.
Journal ArticleDOI
The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint.
Silke Hauf,Richard W. Cole,Sabrina LaTerra,Christine Zimmer,Gisela Schnapp,Rainer Walter,Armin Heckel,Jacques van Meel,Conly L. Rieder,Jan-Michael Peters +9 more
TL;DR: The data suggest that Aurora B is required to generate unattached kinetochores on monooriented chromosomes, which in turn could promote bipolar attachment as well as maintain checkpoint signaling.
Journal ArticleDOI
Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast
Eduardo M. Torres,Tanya Sokolsky,Tanya Sokolsky,Cheryl M. Tucker,Cheryl M. Tucker,Leon Y. Chan,Leon Y. Chan,Monica Boselli,Monica Boselli,Maitreya J. Dunham,Maitreya J. Dunham,Angelika Amon,Angelika Amon +12 more
TL;DR: It is concluded that aneuploidy causes not only a proliferative disadvantage but also a set of phenotypes that is independent of the identity of the individual extra chromosomes.