Tumor suppressor interactions with microtubules: keeping cell polarity and cell division on track

Hernández, Paula; Tirnauer, Jennifer S.

doi:10.1242/dmm.004507

Cited by 26 publications

(20 citation statements)

References 170 publications

(213 reference statements)

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“…These microtubules must be able to extend to the cell cortex, which might be a considerable distance, depending on the geometry of the cell. Thus, their extension might require stabilizing factors, and loss of these stabilizing factors could be a potential mechanism of spindle misorientation in cancer (Hernandez and Tirnauer, 2010). The factors responsible for mediating microtubule stability and microtubule-cell cortex interactions in epithelial cells might include the tumor suppressors discussed in the following section and the force-generating motor protein cytoplasmic dynein (Faulkner et al., 2000;Green et al, 2005;O'Connell and Wang, 2000;Toyoshima and Nishida, 2007a).…”

mentioning

confidence: 99%

Mitotic spindle misorientation in cancer – out of alignment and into the fire

Pease

Tirnauer

2011

Journal of Cell Science

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Patterns of spindle orientationIn most epithelia, the common pattern of spindle orientation is planar, in which the spindle is aligned along the tissue plane, SummaryMitotic spindle orientation can influence tissue organization and vice versa. Cells orient their spindles by rotating them parallel or perpendicular to the cell -and hence the tissue -axis. Spindle orientation in turn controls the placement of daughter cells within a tissue, influencing tissue morphology. Recent findings implicating tumor suppressor proteins in spindle orientation bring to the forefront a connection between spindle misorientation and cancer. In this Commentary, we focus on the role of three major human tumor suppressors -adenomatous polyposis coli (APC), E-cadherin and von Hippel-Lindau (VHL) -in spindle orientation. We discuss how, in addition to their better-known functions, these proteins affect microtubule stability and cell polarity, and how their loss of function causes spindles to become misoriented. We also consider how other cancer-associated features, such as oncogene mutations, centrosome amplification and the tumor microenvironment, might influence spindle orientation. Finally, we speculate on the role of spindle misorientation in cancer development and progression. We conclude that spindle misorientation alone is unlikely to be tumorigenic, but it has the potential to synergize with cancer-associated changes to facilitate genomic instability, tissue disorganization, metastasis and expansion of cancer stem cell compartments. Journal of Cell Scienceparallel to the apical and basal surfaces of the cell (Fernández-Miñán et al., 2007; Fischer et al., 2006; Fleming et al., 2007;Lu et al., 2001) (Fig. 1). Planar spindle orientation leads to the establishment of a cytokinetic furrow that bisects the apical and basal cell surfaces, thereby generating daughter cells that are side by side in the tissue. Both daughter cells retain or re-establish contact with the extracellular matrix (ECM), and they attach to each other along their lateral surfaces (Jinguji and Ishikawa, 1992). Because daughter cells inherit identical contents and ECM attachments, planar spindle orientation can result in symmetric cell division ( Fig. 2A). Loss of planar orientation in tumors could disrupt epithelial tissue morphology by placing daughter cells one on top of the other, creating vertical tissue expansion.Although planar spindle orientation can result in symmetric cell division, it can also lead to asymmetric cell division. For example, in the developing mammalian brain, dividing cells can show planar spindle orientation, but partition cellular components -such as the apical surface and the basal process connecting it to the ECM, unequally -resulting in asymmetric cell division (Kosodo et al., 2004; Kosodo et al., 2008;Siller and Doe, 2009). Uneven distribution of microenvironmental factors, such as gradients of growth factors, could also influence the fates of daughter cells. This might be the case in intestinal crypts, where we found planar spindl...

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confidence: 99%

Mitotic spindle misorientation in cancer – out of alignment and into the fire

Pease

Tirnauer

2011

Journal of Cell Science

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130

103

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“…Basal zebrafish epidermal cell division could be clearly visualized and proceeded with similar kinetics (∼76 min) to those seen in cultured HeLa cells (Mackay et al, 2010). During development this technique could be used to follow mitotic spindle orientation, which can play a crucial role in cell fate decisions (Hernandez and Tirnauer, 2010) and epithelial stratification (Lechler and Fuchs, 2005).…”

Section: Uas Lines To Study Cell Biologymentioning

confidence: 88%

A toolbox to study epidermal cell types in zebrafish

Eisenhoffer

Slattum

Ruíz

et al. 2016

Journal of Cell Science

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Epithelia provide a crucial protective barrier for our organs and are also the sites where the majority of carcinomas form. Most studies on epithelia and carcinomas use cell culture or organisms where highresolution live imaging is inaccessible without invasive techniques. Here, we introduce the developing zebrafish epidermis as an excellent in vivo model system for studying a living epithelium. We developed tools to fluorescently tag specific epithelial cell types and express genes in a mosaic fashion using five Gal4 lines identified from an enhancer trap screen. When crossed to a variety of UAS effector lines, we can now track, ablate or monitor single cells at sub-cellular resolution. Using photo-cleavable morpholino oligonucleotides that target gal4, we can also express genes in a mosaic fashion at specific times during development. Together, this system provides an excellent in vivo alternative to tissue culture cells, without the intrinsic concerns of culture conditions or transformation, and enables the investigation of distinct cell types within living epithelial tissues.

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“…This ‘dynamic instability’ underlies MT-dependent processes, perturbation of which elicits numerous features of neoplastic transformation. EMT appears to render the MT cytoskeleton less stable than in differentiated epithelia 37. Functional loss of tumor suppressor proteins can cause MT disruption, which cooperates with the pleiotropic events underlying EMT 37.…”

Section: Relationship Of Emt To Matmentioning

confidence: 99%

“…EMT appears to render the MT cytoskeleton less stable than in differentiated epithelia 37. Functional loss of tumor suppressor proteins can cause MT disruption, which cooperates with the pleiotropic events underlying EMT 37. Regulators of MT dynamics also affect EMT 383940.…”

Section: Relationship Of Emt To Matmentioning

confidence: 99%

Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

et al. 2014

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Prostate cancer (PCa) remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ‘amoeboid’ phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

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Tumor suppressor interactions with microtubules: keeping cell polarity and cell division on track

Cited by 26 publications

References 170 publications

Mitotic spindle misorientation in cancer – out of alignment and into the fire

Mitotic spindle misorientation in cancer – out of alignment and into the fire

A toolbox to study epidermal cell types in zebrafish

Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

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