Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells

Gomes, Ana Margarida; Orr, Bernardo; Novais-Cruz, Marco; Sousa, Filipe; Macário-Monteiro, Joana; Lemos, Carolina; Ferrás, Cristina; Maiato, Hélder

doi:10.1016/j.cub.2022.08.026

Cited by 22 publications

(31 citation statements)

References 75 publications

(121 reference statements)

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“…However, here we show that in breast cancer cell lines chromosomes that remain misaligned at anaphase onset are the most common mitotic defect. While this article was in review, a second group reported that other cancer cell lines commonly enter anaphase in the presence of misaligned chromosomes ( 59 ), providing independent validation that misaligned chromosomes are a source of CIN. Cells have at least two mechanisms to ensure that lagging chromosomes are segregated into the appropriate daughter cell and therefore do not contribute to CIN ( 32, 44, 58 ).…”

Section: Discussionmentioning

confidence: 89%

“…The ability to extend mitosis indicates that the mitotic checkpoint is functional but not necessarily that the checkpoint is sufficiently robust to perform its biological function of delaying anaphase in the presence of a single unattached kinetochore to prevent CIN. In cells that enter anaphase with misaligned chromosomes after a mitotic delay due to reduction of CENP-E ( 59, 65, 66 ), Mad2-GFP is no longer detected at the kinetochores of misaligned chromosomes by the time the cells enter anaphase and Mad1 is virtually undetectable at kinetochores in early anaphase ( 59 ) and in subsequent micronuclei ( 65 ). These results are consistent with satisfaction of mitotic checkpoint signaling, though they do not explain why the checkpoint is improperly silenced in the presence of chromosomes that are ultimately missegregated.…”

Section: Discussionmentioning

confidence: 99%

“…Here we show that lagging and bridge chromosomes are more potent than misaligned chromosomes in inducing micronuclei. A recent publication came to an opposing conclusion ( 59 ). The likely reason for this is that they only considered cells that “exit mitosis” with misaligned chromosomes—rather than those that enter anaphase with misaligned chromosomes—when calculating the frequency with which misaligned chromosomes produce micronuclei.…”

Section: Discussionmentioning

confidence: 99%

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Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer

Tucker

Bonema

García-Varela

et al. 2023

Cancer Research Communications

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Chromosomal instability (CIN), the persistent reshuffling of chromosomes during mitosis, is a hallmark of human cancers that contributes to tumor heterogeneity and has been implicated in driving metastasis and altering responses to therapy. Though multiple mechanisms can produce CIN, lagging chromosomes generated from abnormal merotelic attachments are the major cause of CIN in a variety of cell lines, and are expected to predominate in cancer. Here, we quantify CIN in breast cancer using a tumor microarray, matched primary and metastatic samples, and patient-derived organoids from primary breast cancer. Surprisingly, misaligned chromosomes are more common than lagging chromosomes and represent a major source of CIN in primary and metastatic tumors. This feature of breast cancers is conserved in a majority of breast cancer cell lines. Importantly, though a portion of misaligned chromosomes align before anaphase onset, the fraction that remain represents the largest source of CIN in these cells. Metastatic breast cancers exhibit higher rates of CIN than matched primary cancers, primarily due to increases in misaligned chromosomes. Whether CIN causes immune activation or evasion is controversial. We find that misaligned chromosomes result in immune-activating micronuclei substantially less frequently than lagging and bridge chromosomes and that breast cancers with greater frequencies of lagging chromosomes and chromosome bridges recruit more stromal tumor-infiltrating lymphocytes (sTILs). These data indicate misaligned chromosomes represent a major mechanism of CIN in breast cancer and provide support for differential immunostimulatory effects of specific types of CIN.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer

Tucker

Bonema

García-Varela

et al. 2023

Cancer Research Communications

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“…Recent evidence also indicated that many more merotelic kinetochore–microtubule attachments than previously thought result in anaphase lagging chromosomes that satisfy the SAC in human cultured cells ( Orr et al, 2021 ; Sen et al, 2021 ), but only rarely result in micronuclei, hinting at the existence of active surveillance and correction mechanisms during anaphase that we are just starting to understand. Interestingly, although most micronuclei in cancer cells derive from anaphase lagging chromosomes that rarely missegregate ( Thompson and Compton, 2011 ), a recent study has shown that misaligned chromosomes that satisfy the SAC often directly missegregate without lagging behind in anaphase and have the highest probability to form micronuclei ( Gomes et al, 2022 ), representing a major source of chromosomal instability in primary and metastatic breast tumors ( Tucker et al, 2023 ; Fig. 1 ).…”

Section: Final Remarks and Outlookmentioning

confidence: 99%

Double-checking chromosome segregation

Maiato

Silva

2023

Journal of Cell Biology

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Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei—key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore–microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability.

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“…The most commonly observed type of chromosome missegregation in cancer cells is lagging chromosomes from merotelic attachments, wherein a single sister chromatid is attached to microtubules emanating from both spindle poles ( Thompson and Compton 2008 ). More recently, unaligned chromosomes that do not converge at the metaphase plate have also been shown to contribute to missegregation in cancer cells ( Gomes et al 2022 ). Ordinarily, such missattachments would be destabilized, and spindle assembly checkpoint (SAC) would delay anaphase until all chromosomes have been fully aligned.…”

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confidence: 99%

Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies

et al. 2023

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Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses. Independently adapted populations converge on complex karyotypes, which over time are refined to contain ever smaller chromosomal changes. Of note, the frequencies of chromosome arm gains in adapted cells correlate with those detected in cancers, suggesting that our cellular adaptation approach recapitulates selective traits that dictate the selection of aneuploidies frequently observed across many cancer types. We further engineered specific aneuploidies to determine the genetic basis behind the observed karyotype patterns. These experiments demonstrated that the adapted and engineered aneuploid cell lines limit CIN by extending mitotic duration. Heterozygous deletions of key SAC and APC/C genes recapitulated the rescue phenotypes of the monosomic chromosomes. We conclude that aneuploidy-induced gene dosage imbalances of individual mitotic regulators are sufficient for altering mitotic timing to reduce CIN.

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Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells

Cited by 22 publications

References 75 publications

Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer

Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer

Double-checking chromosome segregation

Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies

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