The diverse consequences of aneuploidy

Chunduri, Narendra Kumar; Storchová, Zuzana

doi:10.1038/s41556-018-0243-8

Cited by 173 publications

(170 citation statements)

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“…The other pathways found to be more essential in aneuploid cells, were the proteasome function and the DNA damage response ( Fig. 1c and Supplementary Table 3), two cellular processes previously linked to the cellular response to aneuploidy (reviewed in 13,14,35 ).…”

mentioning

confidence: 88%

“…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%

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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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confidence: 88%

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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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“…Aneuploidy can occur naturally; for example, 17% of wild budding yeast isolates harbor aneuploidies and are thought to have evolved mechanisms to tolerate these aneuploid karyotypes (1,2). In most cases, however, aneuploidy is highly detrimental, especially in multicellular animals (3).…”

Section: Introductionmentioning

confidence: 99%

“…Various models have been developed to study aneuploidy in S. cerevisiae. Their analyses led to the conclusions that aneuploidy affects a wide range of cellular processes, such as protein homeostasis, metabolism, and cell wall integrity, and results in an overall decrease in cellular fitness (3,4). However, how aneuploidy affects gene expression has remained controversial.…”

Section: Introductionmentioning

confidence: 99%

The environmental stress response causes ribosome loss in aneuploid yeast cells

Terhorst

Sandikci

Keller

et al. 2020

Preprint

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Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene expression patterns have been reported: the "environmental stress response" (ESR) and the "common aneuploidy gene-expression" (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate and bring clarity to this controversy. We show that the CAGE signature is not an aneuploidy-specific gene expression signature but the result of normalizing the gene expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is amongst the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by downregulating translation capacity.

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“…Whole-chromosome aneuploidy is a nearly-ubiquitous feature of human tumors, though its role in malignancy remains poorly understood Knouse et al 2017;Chunduri and Storchová 2019). Aneuploidy alters the dosage of hundreds or thousands of genes at once, causing proportional changes in the expression of most transcripts on an affected chromosome (Williams et al 2008;Sheltzer et al 2012;Stingele et al 2012;Dürrbaum et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

Vasudevan

Baruah

Smith

et al. 2019

Preprint

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Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis.Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.

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The diverse consequences of aneuploidy

Cited by 173 publications

References 171 publications

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

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

The environmental stress response causes ribosome loss in aneuploid yeast cells

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

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