Microtubules Mechanically Regulate Cell Adhesion Strengthening Via Cell Shape

Elineni, Kranthi Kumar; Gallant, Nathan D.

doi:10.1007/s12195-013-0316-5

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…The increased integrin expression suggested that adhesion strength would be increased in Taxol-resistant cells, but inhibition of tubulin polymerization has previously been shown to effect focal adhesion formation and steady state adhesion strength 30 31 . Since Taxol-resistant cells displayed decreased polymerized tubulin, we next quantified their adhesion strength using a centrifugal-force based adhesion assay to test if the integrin up-regulation in Taxol-resistant clones led to increased adhesion strength.…”

Section: Resultsmentioning

confidence: 99%

Alterations in Ovarian Cancer Cell Adhesion Drive Taxol Resistance by Increasing Microtubule Dynamics in a FAK-dependent Manner

McGrail

Khambhati

et al. 2015

Sci Rep

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Chemorefractory ovarian cancer patients show extremely poor prognosis. Microtubule-stabilizing Taxol (paclitaxel) is a first-line treatment against ovarian cancer. Despite the close interplay between microtubules and cell adhesion, it remains unknown if chemoresistance alters the way cells adhere to their extracellular environment, a process critical for cancer metastasis. To investigate this, we isolated Taxol-resistant populations of OVCAR3 and SKOV3 ovarian cancer cell lines. Though Taxol-resistant cells neither effluxed more drug nor gained resistance to other chemotherapeutics, they did display increased microtubule dynamics. These changes in microtubule dynamics coincided with faster attachment rates and decreased adhesion strength, which correlated with increased surface β1-integrin expression and decreased focal adhesion formation, respectively. Adhesion strength correlated best with Taxol-sensitivity, and was found to be independent of microtubule polymerization but dependent on focal adhesion kinase (FAK), which was up-regulated in Taxol-resistant cells. FAK inhibition also decreased microtubule dynamics to equal levels in both populations, indicating alterations in adhesive signaling are up-stream of microtubule dynamics. Taken together, this work demonstrates that Taxol-resistance dramatically alters how ovarian cancer cells adhere to their extracellular environment causing down-stream increases in microtubule dynamics, providing a therapeutic target that may improve prognosis by not only recovering drug sensitivity, but also decreasing metastasis.

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Section: Resultsmentioning

confidence: 99%

Alterations in Ovarian Cancer Cell Adhesion Drive Taxol Resistance by Increasing Microtubule Dynamics in a FAK-dependent Manner

McGrail

Khambhati

et al. 2015

Sci Rep

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“…The cell tensegrity model proposes a balance between the forces of the tension-bearing actin and compression-resistant microtubules. , A change in these forces by cytoskeletal disruption or modification of adhesion of cells to the substrate has been demonstrated to lead to changes in cell shape, growth, proliferation, and as a result, cell adhesion and fate. − The drastic rearrangement of the actin and microtubule cytoskeleton MSCs cultured on 3D NF could result in a new force balance between the tensile and compressive forces, leading to changes in the shape of the cell and the nucleus that we observed. This in turn, could be one of the factors modulating the differentiation of MSCs on 3D NF.…”

Section: Discussionmentioning

confidence: 99%

“…While the disruption of the microtubule cytoskeleton in differentiated adherent cells has been demonstrated to increase cellular adhesion and contractility via the RhoA activator GEF-H1 without an apparent change in cell area, for the MSCs we cultured on 3D NF, Noc treatment does not elicit the same response. Future experiments will help delineate the role of the microtubule in its function in cell contractility in 2D vs 3D.…”

Section: Discussionmentioning

confidence: 99%

Role of Microtubules in Osteogenic Differentiation of Mesenchymal Stem Cells on 3D Nanofibrous Scaffolds

Meka

Chacko

Ravi

et al. 2017

ACS Biomater. Sci. Eng.

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Human bone marrow mesenchymal stem cells (MSCs) cultured on three-dimensional (3D) nanofibrous scaffolds are known to undergo osteogenic differentiation even in the absence of soluble osteoinductive factors. Although this process of differentiation has been attributed to the shape that cells assume on the fibrous scaffolds, it is unclear how constriction of cell shape would contribute to the differentiation phenotype. Here, we quantitatively compared cell and nuclear morphologies of cells cultured on 3D poly(εcaprolactone) (PCL) nanofibers (NF) and two-dimensional (2D) flat films using confocal fluorescence microscopy. We discovered that while cells on the 2D films exhibited cellular and nuclear morphologies similar to those cultured on tissue culture polystyrene, cells cultured on the 3D NF showed distinct cell and nuclear morphologies, with lower areas and perimeters, but higher aspect ratios. We next tested the effect of treatment of cells with actin-depolymerizing cytochalasin D and microtubule-depolymerizing nocodazole on these morphologies. In both 2D and 3D scaffolds, actin depolymerization brought about gross changes in cell and nuclear morphologies. Remarkably, microtubule depolymerization resulted in a phenotype similar to actin depolymerization in cells cultured on 3D NF alone, indicating a significant role for the microtubule cytoskeleton in the maintenance of cell shape and structure in 3D. The morphological changes of the nucleus that were apparent upon cytoskeletal perturbation were reflected in the organization of heterochromatin in the nucleus, with MSCs on 3D alone exhibiting a differentiation phenotype. Finally, we tested the effect of cytoskeletal depolymerization on mineralization of cells. Again, we observed higher mineralization in cells cultured on 3D NF, which was lost in cells treated with either cytochalasin D or nocodazole. Taken together, our results suggest that both the actin and microtubule cytoskeletons contribute significantly toward maintenance of cell and nuclear shape in cells cultured on 3D scaffolds, and consequently to their osteogenic differentiation.

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Microcontact printing of tissue precursors via geometrically patterned shape-changing hydrogel stamps preserves cell viability and organization

et al. 2017

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Microtubules Mechanically Regulate Cell Adhesion Strengthening Via Cell Shape

Cited by 4 publications

References 31 publications

Alterations in Ovarian Cancer Cell Adhesion Drive Taxol Resistance by Increasing Microtubule Dynamics in a FAK-dependent Manner

Alterations in Ovarian Cancer Cell Adhesion Drive Taxol Resistance by Increasing Microtubule Dynamics in a FAK-dependent Manner

Role of Microtubules in Osteogenic Differentiation of Mesenchymal Stem Cells on 3D Nanofibrous Scaffolds

Microcontact printing of tissue precursors via geometrically patterned shape-changing hydrogel stamps preserves cell viability and organization

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