Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia

Elzen, Nicole den; Buttery, Carmen V.; Maddugoda, Madhavi P.; Ren, Gang; Yap, Alpha S.

doi:10.1091/mbc.e09-01-0023

Cited by 125 publications

(130 citation statements)

References 44 publications

(50 reference statements)

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“…Previous studies have indicated that polarization in stem cells is necessary for asymmetrical divisions 14,15 . However, other studies reported that polarization that is associated with tight junctions or adherens junctions promotes symmetrical divisions [27][28][29] . To determine the polarization patterns of the prostate epithelium, we performed double immunofluorescence of prostate sections with p63, CK8 and antibodies against the polarization molecules Par3 and aPKC.…”

Section: Resultsmentioning

confidence: 98%

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

et al. 2014

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Although symmetrical and asymmetrical divisions of stem cells have been extensively studied in invertebrate and mammalian neural epithelia, their role remains largely unknown in mammalian non-neural epithelial development, regeneration and tumorigenesis. Here, using basal and luminal cell-specific markers and cell lineage tracing transgenic mice, we report that in developing prostatic epithelia, basal and luminal cells exhibit distinct division modes. While basal cells display both symmetric and asymmetric divisions leading to different cell fates, luminal cells only exhibit symmetrical divisions. Examination of cell division modes in prostate-specific Pten-null mice indicates that both luminal and basal cells can be cellular origins for prostate cancer. Furthermore, analysis of Sox2-expressing cells in p63 and Pten-null mice suggests that basal cells contribute to the luminal population and tumorigenesis. These findings provide direct evidence for the existence of a hierarchy of epithelial cell lineages during prostate development, regeneration and tumorigenesis.

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Section: Resultsmentioning

confidence: 98%

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

et al. 2014

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“…109 Dynein/dynactin is also necessary for centrosomal retention and focusing of microtubules, regulation of mitotic spindle positioning and length, and migration of interphase cells. [110][111][112] To conjecture how dynein might contribute to clustering, insight can be gained from current models describing how dynein positions centrosomes and the spindle in nontransformed cells with normal centrosome numbers. In one model, dynein/dynactin is delivered to the cortex during mitosis by microtubule plus-ends.…”

Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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“…1,[4][5][6]. Disrupting E-cadherin's expression or localization has a pronounced impact on a cell's cytoskeletal structure, with changes including misalignment of the microtubule and actin cytoskeletons, defects in cell migration and irregularities in the orientation of the mitotic spindle (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin–Deficient Cells

Telford

Chen

Beetham

et al. 2015

Molecular Cancer Therapeutics

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The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib.Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. Mol Cancer Ther; 14(5); 1213-23. Ó2015 AACR.

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Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia

Cited by 125 publications

References 44 publications

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin–Deficient Cells

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