Tipping Cancer Cells Over the Edge: The Context-Dependent Cost of High Ploidy

Andor, Noemi; Altrock, Philipp M.; Jain, Navami; Gomes, Ana P.

doi:10.1158/0008-5472.can-21-2794

Cited by 5 publications

(5 citation statements)

References 85 publications

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“…These observations suggest that cell type- and/or tissue-specific factors other than the physiological levels of tetraploidy may determine whether WGD prevents or promotes cancer. For instance, nutrient availability may be an important factor for the expansion of tetraploid cell populations in different tissues ( Kimmel et al, 2020 ; Andor et al, 2022 ). Experimental findings have demonstrated that WGD often triggers a p53-mediated cell cycle arrest in non-transformed cells ( Andreassen et al, 2001 ; Kuffer et al, 2013 ), which can be overcome by some tetraploid cells if the p53, Rb, and/or Hippo pathways are disrupted or if cyclin D and/or E are over-expressed ( Andreassen et al, 2001 ; Fujiwara et al, 2005 ; Castedo et al, 2006 ; Ganem et al, 2014 ; Crockford et al, 2017 ; Zeng et al, 2023 ).…”

Section: Is There a Link Between Whole Genome Doubling And Centrosome...mentioning

confidence: 99%

The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

Bloomfield¹,

Cimini²

2023

Front. Cell Dev. Biol.

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An increase in centrosome number is commonly observed in cancer cells, but the role centrosome amplification plays along with how and when it occurs during cancer development is unclear. One mechanism for generating cancer cells with extra centrosomes is whole genome doubling (WGD), an event that occurs in over 30% of human cancers and is associated with poor survival. Newly formed tetraploid cells can acquire extra centrosomes during WGD, and a generally accepted model proposes that centrosome amplification in tetraploid cells promotes cancer progression by generating aneuploidy and chromosomal instability. Recent findings, however, indicate that newly formed tetraploid cells in vitro lose their extra centrosomes to prevent multipolar cell divisions. Rather than persistent centrosome amplification, this evidence raises the possibility that it may be advantageous for tetraploid cells to initially restore centrosome number homeostasis and for a fraction of the population to reacquire additional centrosomes in the later stages of cancer evolution. In this review, we explore the different evolutionary paths available to newly formed tetraploid cells, their effects on centrosome and chromosome number distribution in daughter cells, and their probabilities of long-term survival. We then discuss the mechanisms that may alter centrosome and chromosome numbers in tetraploid cells and their relevance to cancer progression following WGD.

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Section: Is There a Link Between Whole Genome Doubling And Centrosome...mentioning

confidence: 99%

The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

Bloomfield¹,

Cimini²

2023

Front. Cell Dev. Biol.

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“…That ploidy and cancer type are confounded prevents any causal conclusions to be drawn from this analysis. This correlation is however to be expected, because ploidy is highly cancer types specific [72–74].…”

Section: Methodsmentioning

confidence: 99%

Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction

Kimmel

Veith

Bakhoum

et al. 2021

Preprint

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The incidence of somatic copy number alterations (SCNAs) per base pair of the genome is orders of magnitudes larger than that of point mutations. This makes SCNAs phenotypically effective. One mitotic event stands out in its potential to significantly change a cell’s SCNA burden – a chromosome missegregation. We present a general deterministic framework for modeling whole chromosome missegregations and use it to evaluate the possibility of missegregation-induced population extinction (MIE). The model predicts critical curves that separate viable from non-viable populations as a function of their turnover- and mis-segregation rates. Missegregation- and turnover rates estimated for nine cancer types are then compared to these predictions for various biological assumptions. The assumption of heterogeneous misseg-regation rates within a tumor was sufficient to explain the observed data. By contrast, when assuming constant mis-segregation rates, several cancers were located in regions predicted as unviable. Intra-tumor heterogeneity, including heterogeneity in mis-segregation rates, increases as tumors progress. Our predictions suggest that this intra-tumor heterogeneity hinders the chance of success of therapies aimed at MIE.

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“…267,[427][428][429][430][431][432][433][434][435][436][437] Despite these challenges, recent advances suggest promising possibilities for a new, personalized, CIN-specific approach to anti-tumor therapy. 358,406,410,411,[423][424][425][426]438,[451][452][453][454][455] Moreover, considering CIN as the fuel for genomic diversity, it is important to acknowledge the challenges posed by tumor evolution. This suggests that future research could focus on characterizing the common phenotypes that emerge from various CIN routes.…”

Section: Cin Paradoxmentioning

confidence: 99%

The two sides of chromosomal instability: drivers and brakes in cancer

Hosea,

Hillary,

Naqvi

et al. 2024

Sig Transduct Target Ther

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Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the “just-right” model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

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Tipping Cancer Cells Over the Edge: The Context-Dependent Cost of High Ploidy

Cited by 5 publications

References 85 publications

The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction

The two sides of chromosomal instability: drivers and brakes in cancer

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