Spindle Architectural Features Must Be Considered Along With Cell Size to Explain the Timing of Mitotic Checkpoint Silencing

Bloomfield, Mathew; Chen, Jing; Cimini, Daniela

doi:10.3389/fphys.2020.596263

Cited by 7 publications

(17 citation statements)

References 117 publications

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“…We identified distinct aneuploidy recurrence patterns and chromosome-arm genetic interactions in WGD-vs. WGD+ tumors, then validated these results in human cancer cell lines. Furthermore, we studied the relationship between WGD and aneuploidy using genetically-matched systems of human colon cancer cell lines before and after WGD (Kuznetsova et al 2015;Tan et al 2019;Bloomfield et al 2021). Our findings suggest that WGD is a major determinant of aneuploidy evolution in human cancer.…”

Section: Introductionmentioning

confidence: 87%

“…To study the consequence of WGD in human cells, we previously developed geneticallymatched systems of human colon cancer cell lines before and after WGD (Kuznetsova et al 2015;Tan et al 2019;Bloomfield et al 2021).…”

Section: Isogenic Human Cancer Cell Lines Reveal a Causal Relationshi...mentioning

confidence: 99%

“…These cell lines are aneuploid, chromosomally unstable, and exhibit increased tumorigenic behavior and drug resistance (Kuznetsova et al 2015;Tan et al 2019;Bloomfield et al 2021).…”

Section: Isogenic Human Cancer Cell Lines Reveal a Causal Relationshi...mentioning

confidence: 99%

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Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers

et al. 2022

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Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD− tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD− and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD− and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD−/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution. Significance: These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.

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Section: Introductionmentioning

confidence: 87%

Section: Isogenic Human Cancer Cell Lines Reveal a Causal Relationshi...mentioning

confidence: 99%

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Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers

et al. 2022

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“…Regardless of its universal conservation or not, scaling of the rate of microtubule nucleation with the cell surface also represents an efficient way of maintaining a constant spindle assembly duration independently of the final spindle size ( Figure 2 ). Mitotic spindle architecture and geometry were suggested to be critical features influencing the timing of mitotic spindle assembly [ 112 ]. By regulating microtubule organization within the spindle, autocatalytic microtubule nucleation could in fact influence mitotic spindle architecture, and thus its assembly timing.…”

Section: Mechanisms Ensuring Spatial and Temporal Scaling Of The Mitotic Spindlementioning

confidence: 99%

Spatial and Temporal Scaling of Microtubules and Mitotic Spindles

Lacroix

Dumont

2022

Cells

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During cell division, the mitotic spindle, a macromolecular structure primarily comprised of microtubules, drives chromosome alignment and partitioning between daughter cells. Mitotic spindles can sense cellular dimensions in order to adapt their length and mass to cell size. This scaling capacity is particularly remarkable during early embryo cleavage when cells divide rapidly in the absence of cell growth, thus leading to a reduction of cell volume at each division. Although mitotic spindle size scaling can occur over an order of magnitude in early embryos, in many species the duration of mitosis is relatively short, constant throughout early development and independent of cell size. Therefore, a key challenge for cells during embryo cleavage is not only to assemble a spindle of proper size, but also to do it in an appropriate time window which is compatible with embryo development. How spatial and temporal scaling of the mitotic spindle is achieved and coordinated with the duration of mitosis remains elusive. In this review, we will focus on the mechanisms that support mitotic spindle spatial and temporal scaling over a wide range of cell sizes and cellular contexts. We will present current models and propose alternative mechanisms allowing cells to spatially and temporally coordinate microtubule and mitotic spindle assembly.

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“…When it comes to the mitotic spindle, differences in protein quantities may cause variability, but it may also reveal a loosely constrained system [Doncic et al, 2006, Zhang et al, 2013, Barkai and Shilo, 2007, Montevil et al, 2016]. Thus variability in spindle trajectories was often viewed as noise, although it fosters the spindle’s ability to resist or adapt to internal defects like chromosome misattachment and external perturbations like changes in tissue environment [Shahrezaei and Swain, 2008, Knouse et al, 2018, Oegema et al, 2001, Itabashi et al, 2012, Bloomfield et al, 2020, Knouse et al, 2017, Heinrich et al, 2013]. Consistently, variability may increase cellular fitness in cancer [Sarkar et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

Only three principal components account for inter-embryo variability of the spindle length over time

Cunff

Chesneau

Pastezeur

et al. 2023

Preprint

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How does inter-individual variability emerge? When measuring a large number of features per experiment/individual, this question becomes non-trivial. One challenge lies in choosing features to recapitulate high-dimension data. In this paper, we focus on spindle elongation phenotype to highlight how a data-driven approach can help. We showed that only three typical elongation patterns could describe spindle elongation in C.elegansone-cell embryo. We called them archetypes. These archetypes were automatically extracted from the experimental data using principal component analysis (PCA) rather than defined a priori. They accounted for more than 85% of inter-individual variability in a dataset of more than 1600 experiments across more than 100 different experimental conditions (RNAi, mutants, changes in temperature, etc.). The two first archetypes were consistent with standard measures in the field, namely the average spindle length and the spindle elongation rate both in late metaphase and anaphase. However, our archetypes were not strictly corresponding to these manually-set features. The third archetype, accounting for 6% of the variance, was novel and corresponded to a transient spindle shortening in late metaphase. We propose that it is part of spindle elongation dynamics in all conditions. It is reminiscent of the elongation pattern observed upon defects in kinetochore function. Notably, the same archetypes emerged when analysing non-treated embryos only at various temperatures. Interestingly, because these archetypes were not specific to metaphase or anaphase, it implied that spindle elongation around anaphase-onset is sufficient to predict its late anaphase length. We validated this idea using a machine-learning approach. Despite the apparent variability in phenotypes across the various conditions, inter-individual differences between embryos depleted from one cell division-related protein have the same underlying nature as inter-individual differences naturally arising between wild-type embryos. The same conclusion holds when analysing embryos dividing at various temperatures. We thus propose that beyond the apparent complexity of the spindle, only three independent mechanisms account for spindle elongation, and contribute differently in the various conditions, meanwhile, no mechanism is specific to any condition.

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Spindle Architectural Features Must Be Considered Along With Cell Size to Explain the Timing of Mitotic Checkpoint Silencing

Cited by 7 publications

References 117 publications

Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers

Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers

Spatial and Temporal Scaling of Microtubules and Mitotic Spindles

Only three principal components account for inter-embryo variability of the spindle length over time

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