Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Marquis, Carolyn; Fonseca, Cindy L.; Queen, Katelyn A.; Wood, Lisa M; Vandal, Sarah E.; Malaby, Heidi L.H.; Clayton, Joseph E.; Stumpff, Jason

doi:10.1038/s41467-021-21447-2

Cited by 72 publications

(80 citation statements)

References 53 publications

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“…diploid cells 11 . Reasoning that the altered spindle dynamics in CIN tumors may confer sensitivity to inhibition of SAC proteins, Marquis et al 11 systematically knocked down mitotic kinesin proteins in cancer cell lines, measuring the effects on cellular proliferation. The loss of one particular protein, KIF18A, was associated with significantly decreased viability in CIN tumor cells but not their stable, near-diploid counterparts.…”

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confidence: 99%

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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confidence: 99%

Homing in on genomic instability as a therapeutic target in cancer

Bielski

Taylor

2021

Nat Commun

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“…Chromosome oscillation must also be kept in a proper range, as its hyperenhancement by Kif18A depletion was reported to cause KT detachment and micronuclei formation [ 189 , 202 ]. This is of clinical relevance, because Kif18A depletion specifically compromises survival of CIN cancer cells [ 188 , 189 , 190 ]. Whether lowering CIN level by Kif18A depletion through enhancing chromosome oscillation acts synergistically with spindle disruption for cancer therapy is an interesting possibility to be examined.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, multiple types of cancer display elevated levels of Kif18A [ 185 , 186 , 187 ], which suppresses the amplitude of chromosome oscillation [ 152 ]. Recently, three papers reported that CIN or aneuploid cancer cells are vulnerable to Kif18A depletion, which causes spindle defects such as multipolar spindle formation [ 188 , 189 , 190 ]. It was suggested that increased rates of spindle MT polymerization in CIN cells confer an enhanced dependence on the role of Kif18A to limit MT growth [ 190 , 191 ].…”

Section: Chromosome Oscillation Plays a Role In Correction Of Erroneous Kt-mt Attachmentsmentioning

confidence: 99%

“…Recently, three papers reported that CIN or aneuploid cancer cells are vulnerable to Kif18A depletion, which causes spindle defects such as multipolar spindle formation [ 188 , 189 , 190 ]. It was suggested that increased rates of spindle MT polymerization in CIN cells confer an enhanced dependence on the role of Kif18A to limit MT growth [ 190 , 191 ]. One plausible idea is that Kif18A upregulation enables tumor cell survival through spindle assembly in prometaphase at the expense of CIN caused by attenuated chromosome oscillation in metaphase.…”

Section: Chromosome Oscillation Plays a Role In Correction Of Erroneous Kt-mt Attachmentsmentioning

confidence: 99%

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Attenuated Chromosome Oscillation as a Cause of Chromosomal Instability in Cancer Cells

Iemura

Yoshizaki

Kuniyasu

et al. 2021

Cancers

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Chromosomal instability (CIN) is commonly seen in cancer cells, and related to tumor progression and poor prognosis. Among the causes of CIN, insufficient correction of erroneous kinetochore (KT)-microtubule (MT) attachments plays pivotal roles in various situations. In this review, we focused on the previously unappreciated role of chromosome oscillation in the correction of erroneous KT-MT attachments, and its relevance to the etiology of CIN. First, we provided an overview of the error correction mechanisms for KT-MT attachments, especially the role of Aurora kinases in error correction by phosphorylating Hec1, which connects MT to KT. Next, we explained chromosome oscillation and its underlying mechanisms. Then we introduced how chromosome oscillation is involved in the error correction of KT-MT attachments, based on recent findings. Chromosome oscillation has been shown to promote Hec1 phosphorylation by Aurora A which localizes to the spindle. Finally, we discussed the link between attenuated chromosome oscillation and CIN in cancer cells. This link underscores the role of chromosome dynamics in mitotic fidelity, and the mutual relationship between defective chromosome dynamics and CIN in cancer cells that can be a target for cancer therapy.

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“…The top 20 HUB genes were obtained by ranking the degree in cytoHubba. Their functional analysis and KEGG pathway enrichment analysis showed that they played an anti-NSCLC role mainly by participating in the mitosis of tumor cells and regulating cell cycle 11 . But the speci c function should to be veri ed.…”

Section: Discussionmentioning

confidence: 99%

A mRNA-miRNA-lncRNA regulatory network related to potential pathogenesis and prognostic markers of Non- small cell lung cancer

Wang

Yuan

Yang

et al. 2021

Preprint

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Non-small cell lung cancer (NSCLC) is one of the most malignant tumors with the fastest increasing incidence and mortality rate, but the etiology of NSCLC is still not clear. Most of lncRNAs have some structural similarities with mRNAs, suggesting that miRNAs negatively regulate the expression of lncRNAs to affect the occurrence and development of tumor. Therefore, system bioinformatics was used to explore the potential biomarkers and possible pathogenesis of NSCLC in this study. Firstly, all the clinical information and transcriptome data were downloaded from GEO and TCGA databases. R language was used to analyze the differentially expressed genes (DEGs) in NSCLC and normal lung tissues. Then, 50 overlapped DEGs were obtained via Venn database, including 10 down-regulated mRNAs and 40 down-regulated mRNAs. Secondly, the top 20 DEGs were selected for KEGG pathway and GO enrichment analysis. After screening 4 HUB genes related to the survival and prognosis of NSCLC patients, their prognosis models were established. Meanwhile, HUB genes related miRNAs and lncRNAs were screened. Finally, a mRNA-miRNA-lncRNA network related to the survival and prognosis of NSCLC patients was established, including 4 up-regulated mRNAs, 3 up-regulated miRNAs, 10 down-regulated miRNAs, 6 up-regulated lncRNAs and 19 down-regulated lncRNAs. Subject terms: Non-small cell lung cancer, mRNA-miRNA-lncRNA, pathogenesis, prognostic biomarkers.

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Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Cited by 72 publications

References 53 publications

Homing in on genomic instability as a therapeutic target in cancer

Homing in on genomic instability as a therapeutic target in cancer

Attenuated Chromosome Oscillation as a Cause of Chromosomal Instability in Cancer Cells

A mRNA-miRNA-lncRNA regulatory network related to potential pathogenesis and prognostic markers of Non- small cell lung cancer

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