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 195 publications

(231 citation statements)

References 73 publications

(104 reference statements)

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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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“…Two recent studies also identified the KIF18A vulnerability, using orthogonal approaches to identify tumors with ploidy abnormalities and their genetic dependencies based on complementary loss-of-function screens. Cohen-Sharir et al 14 leveraged publicly available genomic data from the Cancer Cell Line Encyclopedia (CCLE) to quantify aneuploidy in cancer cells based on copy number changes affecting whole chromosome arms. Core SAC genes BUB1B and MAD2 ranked as the most preferential individual genetic dependencies in aneuploid cell lines, while the SAC as a whole scored among the most preferentially essential pathways.…”

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Homing in on genomic instability as a therapeutic target in cancer

Bielski

Taylor

2021

Nat Commun

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While genomic instability is a hallmark of cancer, its genetic vulnerabilities remain poorly understood. Identifying strategies that exploit genomic instability to selectively target cancer cells is a central challenge in cancer biology with major implications for anti-cancer drug development.The most common form of genomic instability in cancer is chromosomal instability (CIN), a continuous state of mitotic dysfunction that gives rise to karyotypic abnormalities and aneuploidy. Most human cancers exhibit some degree of CIN with consequences for tumor evolution and prognosis. CIN has been linked to other discrete sources of genomic instability such as whole genome doubling (WGD) 1 and loss-of-function mutations in key tumor suppressor genes leading to dysregulated oncogenic signaling 2 . At the cellular level, CIN precipitates intratumoral heterogeneity and allows tumors to explore greater evolutionary space for fitter subclones that can subsequently expand under selective pressure 3 . CIN also causes the release of genomic DNA into the cytosol which triggers an immune response and activates inflammatory pathways that tumor cells can co-opt to promote metastatic dissemination 4 . These properties have significant clinical ramifications, as CIN is now recognized as a biomarker of poor prognosis across a diverse range of cancer types and both CIN and aneuploidy have also been implicated in multidrug resistance 5 , highlighting the importance of DNA copy number profiling in the clinical setting.CIN is attributed in part to altered dynamics in the mitotic spindle that attaches to chromosomes and orchestrates the accurate separation of genetic material during mitosis. The spindle assembly checkpoint (SAC) safeguards against CIN by delaying the onset of anaphase until chromosomes are properly aligned and attached to the spindle. SAC defects can, therefore, lead to chromosome missegregation errors and aneuploid daughter cells. This phenomenon has been demonstrated in vitro. Treatment with small-molecule inhibitors of the SAC kinase MPS1 can induce CIN in near-diploid cell lines to generate aneuploid cell populations harboring random chromosomal aberrations 6 . Similar effects have been observed in transgenic mouse models with SAC deficiency, where overexpression of core SAC components such as Bub1 or Mad2 yields copy number gains and losses of whole chromosomes and enhanced tumor formation 7,8 . Given the relationship between SAC disruption and CIN, spindle proteins are attractive candidates for therapeutic development in CIN tumors. Nevertheless, therapies that target the underlying mechanisms that lead to CIN have proven elusive. While chemotherapies that target the mitotic spindle are commonly used to treat solid tumors, broad inhibition of spindle function as an anti-cancer therapy is complicated by the potential for toxicity 9,10 .New evidence published recently in Nature Communications suggests that inhibition of a specific spindle protein may decrease cell viability in CIN tumor cells with little or no effect on

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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 195 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

Homing in on genomic instability as a therapeutic target in cancer

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