Asymmetric clustering of centrosomes defines the early evolution of tetraploid cells

Baudoin, Nicolaas C; Nicholson, Joshua M.; Soto, Kimberly; Martı́n, Olga; Chen, Jing; Cimini, Daniela

doi:10.7554/elife.54565

Cited by 30 publications

(56 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following doxycycline washout, centriole number returned to normal over the course of about 10 d ( Figure 1C ), in accordance with previous results documenting centriole reduction after amplification ( Wong et al. , 2015 ; Baudoin et al. , 2020 ; Galofré et al.…”

Section: Resultssupporting

confidence: 92%

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Sala

Farrell

Stearns

2020

MBoC

View full text Add to dashboard Cite

The centriole duplication cycle normally ensures that centriole number is maintained at two centrioles per G1 cell. However, some circumstances can result in an aberrant increase in centriole number—a phenotype that is particularly prevalent in several types of cancer. Following an artificial increase in centriole number without tetraploidization due to transient overexpression of the kinase PLK4, human cells return to a normal centriole number during the proliferation of the population. We examine the mechanisms responsible for this return to normal centriole number at the population level in human retinal pigment epithelial cells. We find that the return to normal centriole number in the population of induced cells cannot be explained by limited duplication of centrioles, instability of extra centrioles, or by grossly asymmetric segregation of extra centrioles in mitosis. However, cells with extra centrioles display heterogenous phenotypes including extended cell cycle arrest, longer interphase durations, and death, which overall result in a proliferative disadvantage relative to normal cells in the population. Although about half of cells with extra centrioles in a population were able to divide, the extent of the disadvantages conferred by other fates is sufficient to account for the observed rate of return to normal centriole number. These results suggest that only under conditions of either positive selection for cells with extra centrioles, continuous generation of such centrioles, or alleviation of the disadvantageous growth phenotypes, would they be maintained in a population.

show abstract

Section: Resultssupporting

confidence: 92%

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Sala

Farrell

Stearns

2020

MBoC

View full text Add to dashboard Cite

show abstract

“…These findings show that tetraploidy has a variable effect on cell and nuclear volumes in DLD-1 cells and that doubling of the genome does not always result in doubling of nuclear size. Finally, we should note that in all 4N clones the majority of cells had normal centrosome numbers, consistent with a recent report that extra centrosomes are rapidly lost in 4N cells via asymmetric centrosome clustering during bipolar cell divisions and selective advantage of cells inheriting a single centrosome (Baudoin et al, 2020 ). During such bipolar divisions with asymmetric centrosome clustering, the chromosomes are partitioned in a bipolar manner and cytokinesis occurs at the midzone.…”

Section: Resultssupporting

confidence: 90%

“…During such bipolar divisions with asymmetric centrosome clustering, the chromosomes are partitioned in a bipolar manner and cytokinesis occurs at the midzone. Therefore, this process is unlikely to explain the size differences we observe in our clones, but it is consistent with the emergence of 4N cell populations in which the vast majority of cells assemble bipolar spindles with normal centrosome numbers (Ganem et al, 2009 ; Godinho et al, 2014 ; Kuznetsova et al, 2015 ; Potapova et al, 2016 ; Viganó et al, 2018 ; Baudoin et al, 2020 ).…”

Section: Resultssupporting

confidence: 70%

“…This idea is supported by a number of observations, including the fact that nearly 40% of all tumors have likely undergone whole genome duplication during their clonal evolution (Zack et al, 2013 ) and that tetraploid, but not diploid, mammary epithelial cells could induce subcutaneous tumors in nude mice (Fujiwara et al, 2005 ). Newly formed tetraploid cells inherit extra centrosomes that promote spindle multipolarity (Chen et al, 2016 ; Baudoin et al, 2020 ), which was proposed as the mechanism underlying the tumorigenic potential of tetraploid cells (Storchova and Pellman, 2004 ). In our 4N clones, however, a majority of cells formed bipolar spindles with a normal centrosome number, consistent with other reports (Ganem et al, 2009 ; Godinho et al, 2014 ; Kuznetsova et al, 2015 ; Potapova et al, 2016 ; Viganó et al, 2018 ) and recent evidence that extra centrosomes are quickly lost through asymmetric centrosome clustering during the evolution of tetraploid cells (Baudoin et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Newly formed tetraploid cells inherit extra centrosomes that promote spindle multipolarity (Chen et al, 2016 ; Baudoin et al, 2020 ), which was proposed as the mechanism underlying the tumorigenic potential of tetraploid cells (Storchova and Pellman, 2004 ). In our 4N clones, however, a majority of cells formed bipolar spindles with a normal centrosome number, consistent with other reports (Ganem et al, 2009 ; Godinho et al, 2014 ; Kuznetsova et al, 2015 ; Potapova et al, 2016 ; Viganó et al, 2018 ) and recent evidence that extra centrosomes are quickly lost through asymmetric centrosome clustering during the evolution of tetraploid cells (Baudoin et al, 2020 ). Our findings suggest that rather than multipolarity resulting from extra centrosomes, relatively subtle variations in spindle geometry, spindle pole size, microtubule abundance, and cell volume can affect mitotic progression and SAC silencing in tetraploid cells.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

2021

Self Cite

View full text Add to dashboard Cite

Mitosis proceeds through a defined series of events that is largely conserved, but the amount of time needed for their completion can vary in different cells and organisms. In many systems, mitotic duration depends on the time required to satisfy and silence the spindle assembly checkpoint (SAC), also known as the mitotic checkpoint. Because SAC silencing involves trafficking SAC molecules among kinetochores, spindle, and cytoplasm, the size and geometry of the spindle relative to cell volume are expected to affect mitotic duration by influencing the timing of SAC silencing. However, the relationship between SAC silencing, cell size, and spindle dimensions is unclear. To investigate this issue, we used four DLD-1 tetraploid (4N) clones characterized by small or large nuclear and cell size. We found that the small 4N clones had longer mitotic durations than the parental DLD-1 cells and that this delay was due to differences in their metaphase duration. Leveraging a previous mathematical model for spatiotemporal regulation of SAC silencing, we show that the difference in metaphase duration, i.e., SAC silencing time, can be explained by the distinct spindle microtubule densities and sizes of the cell, spindle, and spindle poles in the 4N clones. Lastly, we demonstrate that manipulating spindle geometry can alter mitotic and metaphase duration, consistent with a model prediction. Our results suggest that spindle size does not always scale with cell size in mammalian cells and cell size is not sufficient to explain the differences in metaphase duration. Only when a number of spindle architectural features are considered along with cell size can the kinetics of SAC silencing, and hence mitotic duration, in the different clones be explained.

show abstract

Mechanical Torque Promotes Bipolarity of the Mitotic Spindle Through Multi-centrosomal Clustering

2022

View full text Add to dashboard Cite

Intracellular forces shape cellular organization and function. One example is the mitotic spindle, a cellular machine consisting of multiple chromosomes and centrosomes which interact via dynamic microtubule filaments and motor proteins, resulting in complicated spatially dependent forces. For a cell to divide properly, is important for the spindle to be bipolar, with chromosomes at the center and multiple centrosomes clustered into two 'poles' at opposite sides of the chromosomes. Experimental observations show that in unhealthy cells, the spindle can take on a variety of patterns. What forces drive each of these patterns? It is known that attraction between centrosomes is key to bipolarity, but what the prevents the centrosomes from collapsing into a monopolar configuration? Here, we explore the hypothesis that torque rotating chromosome arms into orientations perpendicular to the centrosome-centromere vector promotes spindle bipolarity. To test this hypothesis, we construct a pairwise-interaction model of the spindle. On a continuum version of the model, an integro-PDE system, we perform linear stability analysis and construct numerical solutions which display a variety of spatial patterns. We also simulate a discrete particle model resulting in a phase diagram that confirms that the spindle bipolarity emerges most robustly with torque. Altogether, our results suggest that rotational forces may play an important role in dictating spindle patterning.

show abstract

Asymmetric clustering of centrosomes defines the early evolution of tetraploid cells

Cited by 30 publications

References 63 publications

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

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

Mechanical Torque Promotes Bipolarity of the Mitotic Spindle Through Multi-centrosomal Clustering

Contact Info

Product

Resources

About