Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies

Antmen, Ezgi; Demirci, Utkan; Hasırcı, Vasıf

doi:10.1016/j.colsurfb.2019.110402

Cited by 23 publications

(31 citation statements)

References 57 publications

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“…In our previous study, a detailed comparison of these three cell lines were made and it was shown that the nuclei of the more aggressive cancer cells have a higher capability of deformation. 16 This was also a proof of the ability of metastatic cancer cells migrate through dense ECM by changing the morphology of their nuclei. [35][36][37][38] Figure 1C shows the action mechanisms of the two actin inhibitor drugs Cytochalasin D (CytoD) and Jasplakinolide…”

Section: Resultsmentioning

confidence: 83%

“…Micropillar arrays were designed at METU BIOMATEN and outsourced to be fabricated using photolithography. 13,15,16 The micropillars were in square prism shape, 8 μm tall with 4x4 μm 2 area and 4 μm interpillar gap. Using wafers as a template, polydimethylsiloxane (PDMS) molds were prepared with Sylgard 184 silicone prepolymer and Sylgard 184 curing agent (Dow Corning Company, UK) (10:1 w/w) and cured for 4 h at 70 °C.…”

Section: Preparation Of Micropatterned Pmma Filmsmentioning

confidence: 99%

“…Common shapes used in the fabrication of surface topographies are pores, gratings, wells, pits, cones, posts, pillars, grooves or meshlike structures that can be organized in a regular pattern. [12][13][14][15][16] Several studies have shown that many cell types react strongly to micro and nano features on substrate surfaces. [13][14][15][16][17][18][19] On such surfaces, changes have been reported in the cell behavior such as adhesion, 20,21 alignment, 21-23 morphology (cytoskeletal organization), 17,24 proliferation, 25 viability, 26 gene expression and differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14][15][16] Several studies have shown that many cell types react strongly to micro and nano features on substrate surfaces. [13][14][15][16][17][18][19] On such surfaces, changes have been reported in the cell behavior such as adhesion, 20,21 alignment, 21-23 morphology (cytoskeletal organization), 17,24 proliferation, 25 viability, 26 gene expression and differentiation. 14,27,28 In this study, main hypothesis was that the difference in the stiffness of the nuclei of malignant and benign breast cancer cells can be used as a discriminating factor in cancer detection because of the substantial deformation of the nuclei of the malignant cells that could be quantified through the extent of deformation of the cell nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Nuclear Deformability of Breast Cancer Cells by the Disruption of Actin Filaments

Antmen

Demirci

Hasirci

2019

Preprint

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It is well known that chemical and biomechanical interactions between the nucleus and cytoskeleton are involved in and critical for movement, migration and nuclear positioning of cancer cells. Through nucleo-cytoskeletal coupling, proteins of the LINC complex and the nuclear envelope are capable of transducing cytoplasmic mechanical input across the nuclear membrane; however, their functional importance in the behavior of cancer cells and their nuclei has never been directly tested. In this study, our assumption was that the differences in the malignancies of breast cancer cells are the result of the differences in their nuclear deformation and its expression can be amplified on micropatterned surfaces. Based on this, our hypothesis was that the level of completeness of polymerization of actin filaments can affect nuclear deformability, and as a result, the metastatic capability of the cancer cells. In order to prove this we disrupted the polymerization of the actin filaments by using two drugs, Cytochalasin D and Jasplakinolide, which caused impaired propagation of intracellular forces, prevented nuclear deformation and increased in the expression levels of Lamin A/C and Nesprin-2 in malignant breast cancer cells. Our findings suggest that activity of these two proteins is critical for nucleo-cytoskeletal force transmission. More importantly, actin filament disruption can prevent the distortions in nuclear morphology and as a result avoid the development of cancer metastasis.

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Section: Resultsmentioning

confidence: 83%

Section: Preparation Of Micropatterned Pmma Filmsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of Nuclear Deformability of Breast Cancer Cells by the Disruption of Actin Filaments

Antmen

Demirci

Hasirci

2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our previous study, a detailed comparison of these three cell lines were made and it was shown that the nuclei of the more aggressive cancer cells have a higher capability of deformation. [ 16 ] This was also a proof of the ability of metastatic cancer cells migrate through dense ECM by changing the morphology of their nuclei. [ 35–38 ] Figure 1C shows the action mechanisms of the two actin inhibitor drugs Cytochalasin D (CytoD) and Jasplakinolide (Jasp) used in this study.…”

Section: Resultsmentioning

confidence: 97%

Micropatterned Surfaces Expose the Coupling between Actin Cytoskeleton‐Lamin/Nesprin and Nuclear Deformability of Breast Cancer Cells with Different Malignancies

2020

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Mechanotransduction proteins transfer mechanical stimuli through nucleo‐cytoskeletal coupling and affect the nuclear morphology of cancer cells. However, the contribution of actin filament integrity has never been studied directly. It is hypothesized that differences in nuclear deformability of cancer cells are influenced by the integrity of actin filaments. In this study, transparent micropatterned surfaces as simple tools to screen cytoskeletal and nuclear distortions are presented. Surfaces decorated with micropillars are used to culture and image breast cancer cells and quantify their deformation using shape descriptors (circularity, area, perimeter). Using two drugs (cytochalasin D and jasplakinolide), actin filaments are disrupted. Deformation of cells on micropillars is decreased upon drug treatment as shown by increased circularity. However, the effect is much smaller on benign MCF10A than on malignant MCF7 and MDAMB231 cells. On micropatterned surfaces, molecular analysis shows that Lamin A/C and Nesprin‐2 expressions decreased but, after drug treatment, increased in malignant cells but not in benign cells. These findings suggest that Lamin A/C, Nesprin‐2 and actin filaments are critical in mechanotransduction of cancer cells. Consequently, transparent micropatterned surfaces can be used as image analysis platforms to provide robust, high throughput measurements of nuclear deformability of cancer cells, including the effect of cytoskeletal elements.

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Precision Surface Microtopography Regulates Cell Fate via Changes to Actomyosin Contractility and Nuclear Architecture

et al. 2021

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Cells are able to perceive complex mechanical cues from their microenvironment, which in turn influences their development. Although the understanding of these intricate mechanotransductive signals is evolving, the precise roles of substrate microtopography in directing cell fate is still poorly understood. Here, UV nanoimprint lithography is used to generate micropillar arrays ranging from 1 to 10 µm in height, width, and spacing to investigate the impact of microtopography on mechanotransduction. Using mesenchymal stem cells (MSCs) as a model, stark pattern‐specific changes in nuclear architecture, lamin A/C accumulation, chromatin positioning, and DNA methyltransferase expression, are demonstrated. MSC osteogenesis is also enhanced specifically on micropillars with 5 µm width/spacing and 5 µm height. Intriguingly, the highest degree of osteogenesis correlates with patterns that stimulated maximal nuclear deformation which is shown to be dependent on myosin‐II‐generated tension. The outcomes determine new insights into nuclear mechanotransduction by demonstrating that force transmission across the nuclear envelope can be modulated by substrate topography, and that this can alter chromatin organisation and impact upon cell fate. These findings have potential to inform the development of microstructured cell culture substrates that can direct cell mechanotransduction and fate for therapeutic applications in both research and clinical sectors.

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Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies

Cited by 23 publications

References 57 publications

Loss of Nuclear Deformability of Breast Cancer Cells by the Disruption of Actin Filaments

Loss of Nuclear Deformability of Breast Cancer Cells by the Disruption of Actin Filaments

Micropatterned Surfaces Expose the Coupling between Actin Cytoskeleton‐Lamin/Nesprin and Nuclear Deformability of Breast Cancer Cells with Different Malignancies

Precision Surface Microtopography Regulates Cell Fate via Changes to Actomyosin Contractility and Nuclear Architecture

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