Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

Hwang, Sunyoung; Gustafsson, Helena; O’Sullivan, Ciara K.; Bisceglia, Gianna; Huang, Xinhe; Klose, Christian; Schevchenko, Andrej; Dickson, Robert C.; Cavaliere, Paola; Dephoure, Noah; Torres, Eduardo M.

doi:10.1016/j.celrep.2017.11.103

Cited by 48 publications

(59 citation statements)

References 54 publications

(64 reference statements)

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“…More recently, highly aneuploid colorectal cells were found to be sensitive to an antagonist of ceramide glucosyltransferase due to overabundance of intracellular ceramide, possibly as a result of dysregulated sphingolipid metabolism (Tang et al, 2017). It was also shown that ceramide levels were increased in some aneuploid budding yeast strains and further increasing ceramide levels either genetically or pharmacologically could slow down their proliferation (Hwang et al, 2017). …”

Section: Aneuploidy-associated Stressmentioning

confidence: 99%

Cellular Stress Associated with Aneuploidy

et al. 2018

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Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.

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Section: Aneuploidy-associated Stressmentioning

confidence: 99%

Cellular Stress Associated with Aneuploidy

et al. 2018

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“…In yeast, several aneuploidy-specific cellular vulnerabilities have been described [18][19][20] . For example, aneuploid budding yeast have elevated levels of proteotoxic stress, presumably due to the perturbation of the required stoichiometry of protein complexes 19 .…”

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confidence: 99%

“…For example, aneuploid budding yeast have elevated levels of proteotoxic stress, presumably due to the perturbation of the required stoichiometry of protein complexes 19 . Another example is the increased sensitivity of aneuploid yeast to perturbation of sphingolipid metabolism 20,21 . Although some of these findings were successfully recapitulated in mammalian cells 21,22 , the systematic identification of aneuploidy-induced vulnerabilities remains elusive in human cancer.…”

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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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“…GARP deficiency results in accumulation of sphingolipid synthesis intermediates [151]. Also from this cluster came fatty acid elongase activity ( FEN1/ELO2 and SUR4/ELO3 ), which when deficient leads to reduced ceramide production and phytosphingosine accumulation [152, 153].…”

Section: Resultsmentioning

confidence: 99%

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Santos

Hartman

2019

Preprint

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Background: Saccharomyces cerevisiae represses respiration in the presence of adequate glucose, mimicking the Warburg effect, termed aerobic glycolysis. We conducted yeast phenomic experiments to characterize differential doxorubicin-gene interaction, in the context of respiration vs. glycolysis. The resulting systems level biology about doxorubicin cytotoxicity, including the influence of the Warburg effect, was integrated with cancer pharmacogenomics data to identify potentially causal correlations between differential gene expression and anti-cancer efficacy. Methods: Quantitative high-throughput cell array phenotyping (Q-HTCP) was used to measure cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library, treated with escalating doxorubicin concentrations in fermentable and non-fermentable media. Doxorubicin-gene interaction was quantified by departure of the observed and expected phenotypes for the doxorubicin-treated mutant strain, with respect to phenotypes for the untreated mutant strain and both the treated and untreated reference strain. Recursive expectation-maximization clustering (REMc) and Gene Ontology-based analyses of interactions were used to identify functional biological modules that buffer doxorubicin cytotoxicity, and to characterize their Warburg-dependence. Yeast phenomic data was applied to cancer cell line pharmacogenomics data to predict differential gene expression that causally influences the anti-tumor efficacy, and potentially the anthracycline-associated host toxicity, of doxorubicin. Results: Doxorubicin cytotoxicity was greater with respiration, suggesting the Warburg effect can influence therapeutic efficacy. Accordingly, doxorubicin drug-gene interaction was more extensive with respiration, including increased buffering by cellular processes related to chromatin organization, protein folding and modification, translation reinitiation, spermine metabolism, and fatty acid beta-oxidation. Pathway enrichment was less notable for glycolysis-specific buffering. Cellular processes exerting influence relatively independently, with respect to Warburg status, included homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, and actin cortical patch localization. Causality for differential gene expression associated with doxorubicin cytotoxicity in tumor cells was predicted within the biological context of the phenomic model. Conclusions: Warburg status influences the genetic requirements to buffer doxorubicin toxicity. Yeast phenomics provides an experimental platform to model the complexity of gene interaction networks that influence human disease phenotypes, as in this example of chemotherapy response. High-resolution, systems level yeast phenotyping is useful to predict the biological influence of functional variation on disease, offering the potential to fundamentally advance precision medicine.

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Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

Cited by 48 publications

References 54 publications

Cellular Stress Associated with Aneuploidy

Cellular Stress Associated with Aneuploidy

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

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

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