Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Cohen-Sharir, Yael; McFarland, James M.; Abdusamad, Mai; Marquis, Carolyn; Bernhard, Sara; Kazachkova, Mariya; Tang, Helen; Ippolito, Marica Rosaria; Laue, Kathrin; Zerbib, Johanna; Malaby, Heidi L.H.; Jones, Andrew; Stautmeister, Lisa-Marie; Bockaj, Irena; Wardenaar, René; Lyons, Nicholas; Nagaraja, Ankur K.; Bass, Adam J.; Spierings, Diana C.J.; Foijer, Floris; Beroukhim, Rameen; Santaguida, Stefano; Golub, Todd R.; Stumpff, Jason; Storchová, Zuzana; Ben‐David, Uri

doi:10.1038/s41586-020-03114-6

Cited by 154 publications

(142 citation statements)

References 73 publications

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“…To test this hypothesis, we interrogated the association between NF‐κB activation and the degree of aneuploidy in full‐blown tumors using the cancer cell line encyclopedia [CCLE; (Barretina et al , 2012 ; Ghandi et al , 2019 )]. The degree of aneuploidy was scored in almost 1,000 cell lines in the CCLE as recently described (Cohen‐Sharir et al , 2021 ). We then created two groups of cell lines, a highly aneuploid and a near‐euploid group, defined as the top and bottom quartiles of the number of arm‐level chromosome gains and losses, respectively.…”

Section: Resultsmentioning

confidence: 99%

Aneuploid senescent cells activate NF‐κB to promote their immune clearance by NK cells

et al. 2021

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The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance are thus critical for understanding how cancer cells are recognized and eliminated. Aneuploidy is a hallmark of cancer, and we previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by natural killer (NK) cells in vitro. However, the mechanisms underlying this process remained elusive. Here, using an in vitro NK cell killing system, we show that non‐cell‐autonomous mechanisms in aneuploid cells predominantly mediate their clearance by NK cells. Our data indicate that in untransformed aneuploid cells, NF‐κB signaling upregulation is central to elicit this immune response. Inactivating NF‐κB abolishes NK cell‐mediated clearance of untransformed aneuploid cells. In cancer cell lines, NF‐κB upregulation also correlates with the degree of aneuploidy. However, such upregulation in cancer cells is not sufficient to trigger NK cell‐mediated clearance, suggesting that additional mechanisms might be at play during cancer evolution to counteract NF‐κB‐mediated immunogenicity.

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Section: Resultsmentioning

confidence: 99%

Aneuploid senescent cells activate NF‐κB to promote their immune clearance by NK cells

et al. 2021

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“…We examined data from a collection of 367 human cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) with matched DNA copy number, RNA expression and protein expression data [49][50][51][52][53][54] (Supplementary Data 1). We used a recently-described dataset in which each chromosome arm in a cell line was classified as "lost", "gained", or "neutral", relative to that cancer cell line's basal ploidy 55 . We calculated mean RNA and protein expression differences along each chromosome arm between cell lines with neutral ploidy for that arm and cell lines in which that arm was either gained or lost (Supplementary Data 2).…”

Section: Mean Protein Expression Increases Upon Chromosome Gain and Decreases Upon Chromosome Lossmentioning

confidence: 99%

Extensive protein dosage compensation in aneuploid human cancers

2021

Preprint

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Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we have conducted an analysis of hundreds of human cancer cell lines with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

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“…Finally, it remains an open debate if the proper way to attack cancer cells is by extending a mitotic poison-induced arrest, or, alternatively, if a better strategy is to try and destroy spindle checkpoint function and force cancers cells to exit mitosis pre-maturely in the presence of a mitotic poison, leading to catastrophic levels of chromosome mis-segregation that even cancer cells cannot tolerate. The argument for this approach has recently been buttressed by the observation that as cancer cells become more and more aneuploid, which tends to correlate with the stage and aggressiveness of many cancers, they also become more and more sensitive to the removal of mitotic spindle checkpoint function [ 37 ]. Thus, rather than enhancing the checkpoint-dependent arrest, a better strategy may be to disrupt the mitotic spindle checkpoint to make the cell cycle delay as short as possible.…”

Section: Discussionmentioning

confidence: 99%

Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons

Schuyler

Chen

2021

IJMS

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Research on the budding yeast Saccharomyces cerevisiae has yielded fundamental discoveries on highly conserved biological pathways and yeast remains the best-studied eukaryotic cell in the world. Studies on the mitotic cell cycle and the discovery of cell cycle checkpoints in budding yeast has led to a detailed, although incomplete, understanding of eukaryotic cell cycle progression. In multicellular eukaryotic organisms, uncontrolled aberrant cell division is the defining feature of cancer. Some of the most successful classes of anti-cancer chemotherapeutic agents are mitotic poisons. Mitotic poisons are thought to function by inducing a mitotic spindle checkpoint-dependent cell cycle arrest, via the assembly of the highly conserved mitotic checkpoint complex (MCC), leading to apoptosis. Even in the presence of mitotic poisons, some cancer cells continue cell division via ‘mitotic slippage’, which may correlate with a cancer becoming refractory to mitotic poison chemotherapeutic treatments. In this review, knowledge about budding yeast cell cycle control is explored to suggest novel potential drug targets, namely, specific regions in the highly conserved anaphase-promoting complex/cyclosome (APC/C) subunits Apc1 and/or Apc5, and in a specific N-terminal region in the APC/C co-factor cell division cycle 20 (Cdc20), which may yield molecules which block ‘mitotic slippage’ only in the presence of mitotic poisons.

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Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Abstract: U. (2021).Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature, 590(7846).

Cited by 154 publications

References 73 publications

Aneuploid senescent cells activate NF‐κB to promote their immune clearance by NK cells

Aneuploid senescent cells activate NF‐κB to promote their immune clearance by NK cells

Extensive protein dosage compensation in aneuploid human cancers

Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons

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