Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells

Rhys, Alexander D.; Monteiro, Pedro T.; Smith, Christopher M.; Vaghela, Malti; Arnandis, Teresa; Kato, Takuya; Leitinger, Birgit; McAinsh, Andrew D.; Charras, Guillaume; Godinho, Susana A.

doi:10.1083/jcb.201704102

Cited by 64 publications

(111 citation statements)

References 56 publications

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“…Besides stochastic effects, other aspects of the spindle mechanics will have to be considered to make the model less simplistic. Those include influence of merotelic errors of assembly on the force balance (25), space-dependent motor regulation (15), viscoelastic properties of the spindle (23), and role of the cortex flow in bringing CSs together (73), not to mention biophysical details of the magnitudes and spatial dependencies of the forces in the spindle that remain under-researched (22,47,74).…”

Section: Discussionmentioning

confidence: 99%

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

Chatterjee

Sarkar

Zhu

et al. 2019

Preprint

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To segregate chromosomes in mitosis, cells assemble mitotic spindle, a molecular machine with centrosomes at two opposing cell poles and chromosomes at the equator. Microtubules and molecular motors connect the poles to kinetochores, specialized protein assemblies on the centromere regions of the chromosomes. Bipolarity of the spindle is crucial for the proper cell division, and two centrosomes in animal cells naturally become two spindle poles. Cancer cells are often multi-centrosomal, yet they are able to assemble bipolar spindles by clustering centrosomes into two spindle poles. Mechanisms of this clustering are debated. In this study, we computationally screen effective forces between a) centrosomes, b) centrosomes and kinetochores, c) centrosomes and chromosome arms, d) centrosomes and cell cortex, to understand mechanics that determines three-dimensional spindle architecture. To do this, we use stochastic Monte Carlo search for stable mechanical equilibria in effective energy landscape of the spindle. We find that the following conditions have to be met to robustly assemble the bipolar spindle in a multi-centrosomal cell: 1) strengths of centrosomes' attraction to each other and to the cell cortex have to be proportional to each other; 2) strengths of centrosomes' attraction to kinetochores and repulsion from the chromosome arms have to be proportional to each other. We also find that three other spindle configurations emerge if these conditions are not met: a) collapsed, b) monopolar, c) multipolar spindles, and the computational screen reveal mechanical conditions for these abnormal spindles. Running title: Multi-centrosomal clusteringSignificance statement: To segregate chromosomes, cells assemble bipolar mitotic spindle. Multiple mechanical forces generated by microtubules and molecular motors in the spindle govern the spindle architecture, but it is unclear what force balances support the bipolarity of the spindle. This problem is especially difficult and important in cancer cells, which often have multiple centrosomes that somehow are able to cluster into two spindle poles. By using stochastic energy minimization in an effective energy landscape of the spindle and computationally screening forces, we find mechanical conditions for mono-, multi-and bi-polar spindles. We predict how microtubule and motor parameters have to be regulated in mitosis in multi-centrosomal cells.

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Section: Discussionmentioning

confidence: 99%

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

Chatterjee

Sarkar

Zhu

et al. 2019

Preprint

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“…Centrosome aberrations are also prominent in cancers, including pre‐invasive in situ carcinomas (Lingle et al , ; Pihan et al , ; Guo et al , ), suggesting that they contribute actively to carcinogenesis (Lingle et al , ; Nigg, ; Pujana et al , ; Zyss & Gergely, ; Godinho & Pellman, ; Gonczy, ). Interestingly, cancer cells adapt to centrosome aberrations in multiple ways, notably through clustering of supernumerary centrosomes (Nigg, ; Quintyne et al , ; Rhys et al , ). Best documented is the influence of centrosome aberrations on chromosomal instability, a hallmark of cancer (Ganem et al , ; Silkworth et al , ), and increasing evidence also suggests an impact on tissue architecture (Nigg, ; Godinho & Pellman, ; Kazazian et al , ; Raff & Basto, ).…”

Section: Introductionmentioning

confidence: 99%

Structural centrosome aberrations promote non‐cell‐autonomous invasiveness

et al. 2018

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Centrosomes are the main microtubule‐organizing centers of animal cells. Although centrosome aberrations are common in tumors, their consequences remain subject to debate. Here, we studied the impact of structural centrosome aberrations, induced by deregulated expression of ninein‐like protein (NLP), on epithelial spheres grown in Matrigel matrices. We demonstrate that NLP‐induced structural centrosome aberrations trigger the escape (“budding”) of living cells from epithelia. Remarkably, all cells disseminating into the matrix were undergoing mitosis. This invasive behavior reflects a novel mechanism that depends on the acquisition of two distinct properties. First, NLP‐induced centrosome aberrations trigger a re‐organization of the cytoskeleton, which stabilizes microtubules and weakens E‐cadherin junctions during mitosis. Second, atomic force microscopy reveals that cells harboring these centrosome aberrations display increased stiffness. As a consequence, mitotic cells are pushed out of mosaic epithelia, particularly if they lack centrosome aberrations. We conclude that centrosome aberrations can trigger cell dissemination through a novel, non‐cell‐autonomous mechanism, raising the prospect that centrosome aberrations contribute to the dissemination of metastatic cells harboring normal centrosomes.

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“…Extra centrosomes can be generated in diploid NBs by Plk4/Sak over-expression (OE) [7]. In SakOE NBs as in other cells containing extra centrosomes, the minus-end directed kinesin Ncd (Drosophila ortholog of HSET) plays an essential role in promoting centrosome clustering [18,31]. We tested whether Ncd was also contributing to the initial clustering observed in polyploid NBs.…”

Section: Ncd/hset Is Required But Is Not Sufficient To Fully Clustermentioning

confidence: 99%

“…We tested whether DNA could function as a physical barrier that could maintain multiple spindle poles away from each other. Indeed, it has been shown that Ncd requires a minimal distance to promote clustering through cross-linking of antiparallel MTs [31]. We first established an in-silico approach.…”

Section: Abnormal Dna Content and Shape Inhibit Spindle Pole Clusteringmentioning

confidence: 99%

Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells

Goupil

Nano

Letort

et al. 2019

Preprint

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Whole genome duplications (WGDs) are found in a variety of tumors and are associated with chromosomal instability (CIN) and poor prognosis [1,2]. When induced experimentally, through cytokinesis failure, polyploid cells generate tumors [3]. Cytokinesis failure results in the accumulation of double DNA content, but also of cytoplasmic organelles, such as centrosomes, which are the major microtubule (MT) organizing centers of animal cells. Importantly, even if there is a correlation between polyploidy and CIN [4], the underlying mechanisms generating error-prone mitosis in cells with extra DNA and extra centrosomes are not known. When considering polyploid mitosis, it is essential to take into account the increase in MT nucleation due to the presence of extra centrosomes and extra DNA. The presence of supernumerary centrosomes in a cell, centrosome amplification [5], is associated with mitotic spindle multipolarity and CIN [ [6][7][8][9]. Importantly, additional MTs can be nucleated from the chromatin (chromatin mediated pathway-CMP) or from pre-existing MTs-through the Augmin pathway. We hypothesized that the increase in DNA and centrosome content in a cell could lead to an increased MT mass, which might account for abnormal mitosis described in polyploid cells [4,10,11,12]. Using genetics, live imaging and modeling approaches, we investigated the mechanisms establishing multipolarity in vivo in polyploid cells. We found that MT nucleation from the centrosomes is the major contributor to multipolarity, while other pathways seem to play minor roles. Unexpectedly, we found that even if Ncd/HSET, plays an essential role in promoting centrosome clustering in early mitosis, the increase in chromosome mass associated with cytokinesis failure functions as a barrier to centrosome clustering into two main poles. Our work provides a mechanistic link between polyploidy and the generation of CIN.

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Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells

Cited by 64 publications

References 56 publications

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

Structural centrosome aberrations promote non‐cell‐autonomous invasiveness

Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells

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