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Aneuploidy as a promoter and suppressor of malignant growth

Abstract

Aneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell’s genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy’s distinct roles as both a tumour promoter and an anticancer vulnerability.

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Fig. 1: Generating aneuploidy in cell lines and in mouse models.
Fig. 2: Aneuploidy and tumorigenesis.
Fig. 3: Interrelationship between aneuploidy-associated and CIN-associated phenotypes.
Fig. 4: Aneuploidy can have protumorigenic and tumour-inhibiting effects on the immune system.

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Acknowledgements

The authors thank members of the Sheltzer laboratory for helpful comments on the manuscript.

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All authors contributed to all aspects of the article (researching data, substantially contributing to discussion of content, and writing, reviewing and editing the manuscript before submission).

Corresponding author

Correspondence to Jason M. Sheltzer.

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Competing interests

J.M.S. is a co-founder of Meliora Therapeutics, is a member of the Scientific Advisory Board of Tyra Biosciences and has received consulting fees from Merck and Ono Pharmaceutical Co. The other authors declare no competing interests.

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Dedication

J.M.S. dedicates this article to the memory of Angelika Amon, for her outstanding mentorship, her passion for tackling unorthodox questions and her pioneering research into the consequences of aneuploidy.

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Nature Reviews Cancer thanks A. Holland, G. Kops and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Polyploidy

Describing an abnormal number of chromosomes, such that a cell’s karyotype is an integer multiple of the haploid complement greater than 2.

Chromosomal instability

(CIN). An abnormally high rate of chromosomal mis-segregation that may result in aneuploidy.

Microcell-mediated chromosome transfer

Technique involving the transfer of specific donor chromosomes into recipient cell lines as a means of creating aneuploid cells.

Spindle-assembly checkpoint

Cell cycle checkpoint that maintains genome stability by ensuring proper chromosome attachment at the kinetochore via anchorage to the microtubule spindle apparatus before the initiation of anaphase.

Cre–lox-mediated recombination

A technique used to introduce site-specific deletions, insertions, translocations and inversions within chromosomes.

Robertsonian translocations

Translocations in which two acrocentric chromosomes fuse to share a single centromere.

Proteotoxic stress

Impaired cell function arising as a result of defective protein translation, folding and/or turnover.

Epithelial–mesenchymal transition

The process by which epithelial cells transition into mesenchymal cells through the loss of cell polarity and cell–cell adhesion and the subsequent gain of migratory and invasive abilities.

Mesenchymal–epithelial transition

The process by which mesenchymal cells lose their migratory and invasive properties and transition into epithelial cells capable of increased cell–cell adhesion.

Apc Min/+ mice

Mice that develop spontaneous intestinal adenomas due to a point mutation in the mouse homologue of the APC gene. They are frequently used as models for intestinal tumorigenesis.

Hypomorphic

A mutation resulting in the reduction, but not the complete loss, of gene function.

Cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING)

Immune system pathway that detects cytosolic DNA and elicits a downstream inflammatory response to aid in immune clearance.

Down syndrome

Genetic disorder associated with developmental and intellectual delays due to the added presence of a third copy of chromosome 21.

Ts65Dn mouse

A commonly used genetic mouse model for Down syndrome that is segmentally trisomic for part of mouse chromosome 16, which encodes genes homologous to those found on human chromosome 21.

Pearson correlation coefficient

Statistic measuring the strength of association between two variables.

Replication stress

A cellular state in which the fidelity of DNA replication is compromised, often characterized by the frequent collapse of the replication fork.

Hyper-recombination

A cellular state defined by elevated levels of recombination.

Senescence

Process by which proliferating cells cease dividing due to extracellular or intracellular stress and enter a state of permanent cell cycle arrest.

Senescence-associated secretory phenotype

(SASP). Unique secretome consisting of chemokines, cytokines, growth factors and immune regulators that are released into the microenvironment by senescent cells.

MMTV–PyMT mice

Common model of metastatic breast cancer in which the mouse mammary tumour virus (MMTV) promotor drives the expression of the polyomavirus middle T antigen (PyMT), leading to spontaneous and rapid tumorigenesis in mouse mammary epithelial cells.

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Vasudevan, A., Schukken, K.M., Sausville, E.L. et al. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer 21, 89–103 (2021). https://doi.org/10.1038/s41568-020-00321-1

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