Cellular Stress Associated with Aneuploidy

Zhu, Jin; Tsai, Hung-Ji; Gordon, Molly R.; Li, Rong

doi:10.1016/j.devcel.2018.02.002

Cited by 181 publications

(186 citation statements)

References 127 publications

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“…Chromosomal instability is related to drug resistance, metastasis, and poor prognosis, which may be caused by intratumor heterogeneity (Figure ); CIN leads to continuous chromosome missegregation and formation of a variety of aneuploid cells. This increases the chance of gaining additional oncogenic potential, even though aneuploid cells often suffer from various stresses that reduce their cellular fitness . Chromosome missegregation promotes not only changes in chromosome number, but also structural changes, such as deletion, amplification, and translocation.…”

Section: Tetraploidy and Cancermentioning

confidence: 99%

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Tetraploidy in cancer and its possible link to aging

et al. 2018

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Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, is often seen as a natural physiological condition but is also frequently seen in pathophysiological conditions such as cancer. Tetraploidy facilitates chromosomal instability (CIN), which is an elevated level of chromosomal loss and gain that can cause production of a wide variety of aneuploid cells that carry structural and numerical aberrations of chromosomes. The resultant genomic heterogeneity supposedly expedites karyotypic evolution that confers oncogenic potential in spite of the reduced cellular fitness caused by aneuploidy. Recent studies suggest that tetraploidy might also be associated with aging; mice with mutations in an intermediate filament protein have revealed that these tetraploidy‐prone mice exhibit tissue disorders associated with aging. Cellular senescence and its accompanying senescence‐associated secretory phenotype have now emerged as critical factors that link tetraploidy and tetraploidy‐induced CIN with cancer, and possibly with aging. Here, we review recent findings about how tetraploidy is related to cancer and possibly to aging, and discuss underlying mechanisms of the relationship, as well as how we can exploit the properties of cells exhibiting tetraploidy‐induced CIN to control these pathological conditions.

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Section: Tetraploidy and Cancermentioning

confidence: 99%

“…This increases the chance of gaining additional oncogenic potential, even though aneuploid cells often suffer from various stresses that reduce their cellular fitness. 45 Chromosome missegregation promotes not only changes in chromosome number, but also structural changes, such as deletion, amplification, and translocation.…”

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confidence: 99%

Tetraploidy in cancer and its possible link to aging

et al. 2018

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“…The folding of chromosomes in preparation for mitosis is the most profound structural change the genome undergoes throughout a cell's lifetime (Antonin and Neumann, 2016). Mitotic condensation is linked to successful cell division and cell cycle progression in a functional and regulatory manner and its failure can be costly, leading to lagging chromosomes and aneuploidy (Gordon et al, 2012;Zhu et al, 2018). Much effort has been made to define the molecular basis of the condensation process and bridge the cytogenetic features of mitotic chromosomes with molecular-level understanding of the chromatin and scaffolding proteins that comprise them.…”

Section: Introductionmentioning

confidence: 99%

Common fragile sites are characterised by faulty condensin loading after replication stress

Boteva

Nozawa

Naughton

et al. 2018

Preprint

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Cells coordinate interphase to mitosis transition but recurrent cytogenetic lesions appear at common fragile sites (CFSs) in a tissue-specific manner following replication stress, marking regions of instability in cancer. Despite such a distinct defect no model fully explains their molecular configuration.We show that CFSs are characterised by impaired chromatin folding manifested as disrupted mitotic structures visible using molecular FISH probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist atCFSs throughout the cell cycle and mitosis. Subsequently cytogenetic and molecular lesions arise due to faulty condensin loading at CFSs, through a defect in condensin I mediated compaction and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS formation, concomitantly providing an environment for MIDAS, which, if not resolved, result in chromosome instability.

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“…While some aneuploidyinduced dependencies would be specific to the altered chromosome 4,[9][10][11][12] , others may be the consequence of more general cellular burdens associated with an abnormal number of chromosomes, independently of specific karyotypes. Indeed, aneuploidy causes various types of cellular stress responses: proteotoxic, metabolic, replicative, mitotic and hypo-osmotic 4,8,13,14 . Consistent with a general cellular response to aneuploidy, introduction of aneuploidy into mammalian cells activated transcriptional programs that were independent of the specific chromosome 15,16 .…”

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confidence: 99%

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Cohen-Sharir

McFarland

Abdusamad

et al. 2020

Preprint

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Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between neardiploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

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Cellular Stress Associated with Aneuploidy

Cited by 181 publications

References 127 publications

Tetraploidy in cancer and its possible link to aging

Tetraploidy in cancer and its possible link to aging

Common fragile sites are characterised by faulty condensin loading after replication stress

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

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