Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Quinton, Ryan J.; DiDomizio, Amanda; Vittoria, Marc A.; Kotýnková, Kristýna; Ticas, Carlos J.; Patel, Sheena; Koga, Yusuke; Vakhshoorzadeh, Jasmine; Hermance, Nicole; Kuroda, Taruho S.; Parulekar, Neha; Taylor, Alison M.; Manning, Amity L.; Campbell, Joshua D.; Ganem, Neil J.

doi:10.1038/s41586-020-03133-3

Cited by 182 publications

(248 citation statements)

References 54 publications

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“…This raises the possibility that polyploidy may promote primary tumor growth in the absence of an adaptive immune system, but slow primary tumor growth in immunocompetent mice, which would be consistent with previous findings [8,27]. Indeed, recent studies examining human tumors have shown that established aneuploid tumors actually have fewer adaptive immune cells and diminished host immune responses [39,40] suggesting that these tumors evolve immune escape mechanisms. Together these results suggest the consequences of polyploidy, including aneuploidy, shape interactions between tumors and the microenvironment, leading to changes in gene expression that are likely to influence tumor growth and characteristics.…”

Section: Discussionsupporting

confidence: 86%

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Newcomb

Dean

Alvarez

2021

Preprint

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Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

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Section: Discussionsupporting

confidence: 86%

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Newcomb

Dean

Alvarez

2021

Preprint

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“…The second study from Quinton et al 15 examined the genetic dependencies conferred by whole genome doubling (WGD) in cancer cell lines. WGD is a common genomic aberration in human cancer that is associated with enhanced fitness and poor prognosis, yet relatively little is known about its concomitant genetic vulnerabilities.…”

mentioning

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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“…The most frequently observed increased karyotypes approach tetraploidy, which led to the hypothesis that such 'near-tetraploid' tumors had undergone a whole-genome doubling (WGD) event during tumor progression and subsequently experienced a small net loss of chromosomes 1,2 . Recent bioinformatic analyses support this hypothesis, showing that WGD events are prevalent in a diverse set of solid tumors, and nearly 37% of all solid tumors measured, including 40% of melanomas, experienced at least one WGD event in their progression 3,4 . Based on these analyses, WGD frequently occurs early in tumor formation, and the presence of tetraploid cells in some pre-cancerous lesions, such as Barrett's esophagus and lesions of the cervix and kidney, suggests that WGD may even precede frank tumor formation in some tissues [5][6][7][8] Tetraploidy was also observed in hyperplastic lesions of the pancreas 9 , in localized prostate cancer [10][11][12] and some colon adenomas 13,14 , and for certain malignancies, such as oral tumors 15 , tetraploidy is a strong predictor of malignant transformation.…”

Section: Introductionmentioning

confidence: 93%

Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

Darp

Vittoria

Ganem

et al. 2021

Preprint

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Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various protumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAFV600E, the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAFV600E causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600E activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600E activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity.

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Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Cited by 182 publications

References 54 publications

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Homing in on genomic instability as a therapeutic target in cancer

Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

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