Tumor cell nuclei soften during transendothelial migration

Roberts, Anya Burkart.; Zhang, Jitao; Singh, Vijay Raj; Nikolić, Miloš; Moeendarbary, Emad; Kamm, Roger D.; So, Peter T. C.; Scarcelli, Giuliano

doi:10.1016/j.jbiomech.2021.110400

Cited by 52 publications

(37 citation statements)

References 50 publications

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“…More specifically, we have shown that by increasing the simulation time, the nucleus undergoes significant self deformation and it acquires a 'peanut' shape by embracing the micropillar as it has been reported in [11][12][13][14]. Such a phenomenon is exacerbated when the nuclear lamina is ablated (i.e., reducing the Young modulus) and it confirms data according to which tumor cells are able to adjust their mechanical properties in order to invade healthy tissues [43].…”

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Nuclear Stress-Strain State over Micropillars: A Mechanical In silico Study

Allena¹,

Aubry²

2022

Molecular &Amp; Cellular Biomechanics

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Cells adapt to their environment and stimuli of different origin. During confined migration through sub-cellular and sub-nuclear pores, they can undergo large strains and the nucleus, the most voluminous and the stiffest organelle, plays a critical role. Recently, patterned microfluidic devices have been employed to analyze the cell mechanical behavior and the nucleus self-deformations. In this paper, we present an in silico model to simulate the interactions between the cell and the underneath microstructured substrate under the effect of the sole gravity. The model lays on mechanical features only and it has the potential to assess the contribution of the nuclear mechanics on the cell global behavior. The cell is constituted by the membrane, the cytosol, the lamina, and the nucleoplasm. Each organelle is described through a constitutive law defined by specific mechanical parameters, and it is composed of a fluid and a solid phase leading to a viscoelastic behavior. Our main objective is to evaluate the influence of such mechanical components on the nucleus behavior. We have quantified the stress and strain distributions in the nucleus, which could be responsible of specific phenomena such as the lamina rupture or the expression of stretch-sensitive proteins.

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Section: Discussionsupporting

confidence: 85%

“…7c), which correspond to a decrease of the lamina Young's modulus in the numerical simulation. This confirms specific experimental observations according to which tumor cells are able to soften their nucleus and adjust their mechanical properties in order to facilitate extravasation [43].…”

Section: Comparison With Experimental Datasupporting

confidence: 87%

Nuclear Stress-Strain State over Micropillars: A Mechanical In silico Study

Allena¹,

Aubry²

2022

Molecular &Amp; Cellular Biomechanics

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“…The mechanical properties of the nucleus have been reported to be altered in cancer cells [16]. Several studies have suggested that nuclear softening increases the invasiveness of tumor cells [16,187,188], and a recent study found that cancer cell nuclei soften during migration through an endothelial cell layer [189]. Nonetheless, the stiffness of PDAC cells has been shown to positively correlate with invasiveness [190].…”

Section: Nuclear Mechanicsmentioning

confidence: 99%

“…In contrast, Lamin A is increased in hepatocellular carcinoma and invasive prostate cancer, and acts as a positive regulator of cell growth and migration in these cancer cell types [287,288], illustrating that Lamin A/C loss is not a universal feature of cancer. Although decreased Lamin A/C has been linked with softer nuclei and increased migration or invasiveness of cancer cells [189,289], a study comparing four PDAC cell lines found that invasiveness was positively correlated with increased stiffness and Lamin A levels among these cells [190]. Clearly, much more needs to be learned about the interrelationships between nuclear morphology, gene expression, nuclear stiffness, and genetic instability in pancreatic cancer.…”

Section: Unanswered Questions and Future Directionsmentioning

confidence: 99%

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

Flores

Tader

Tolosa

et al. 2021

Cells

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Changes in nuclear shape have been extensively associated with the dynamics and functionality of cancer cells. In most normal cells, nuclei have a regular ellipsoid shape and minimal variation in nuclear size; however, an irregular nuclear contour and abnormal nuclear size is often observed in cancer, including pancreatic cancer. Furthermore, alterations in nuclear morphology have become the ‘gold standard’ for tumor staging and grading. Beyond the utility of altered nuclear morphology as a diagnostic tool in cancer, the implications of altered nuclear structure for the biology and behavior of cancer cells are profound as changes in nuclear morphology could impact cellular responses to physical strain, adaptation during migration, chromatin organization, and gene expression. Here, we aim to highlight and discuss the factors that regulate nuclear dynamics and their implications for pancreatic cancer biology.

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“…This is why in many cases, evaluating the relative changes of the elastic modulus is an extremely effective strategy, eventually more informative and surely more robust than providing its absolute value (Baldini et al 2019). Accordingly, the micromechanical modifications probed by Brillouin have been used to evaluate the effectiveness of drugs in tumor spheroids (Margueritat et al 2019), in phenotyping healthy and tumor cells (Mattana et al 2018), in the evaluation of nuclear mechanics within intact cells (Zhang et al 2017(Zhang et al , 2020 and of nuclear softening during transendothelial migration (Roberts et al 2021). These few examples, in which the capability offered by micro-Brillouin spectroscopy was used in the mechanobiology field, clarify Fig.…”

mentioning

confidence: 99%

Non-contact elastography methods in mechanobiology: a point of view

et al. 2021

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In recent decades, mechanobiology has emerged as a novel perspective in the context of basic biomedical research. It is now widely recognized that living cells respond not only to chemical stimuli (for example drugs), but they are also able to decipher mechanical cues, such as the rigidity of the underlying matrix or the presence of shear forces. Probing the viscoelastic properties of cells and their local microenvironment with sub-micrometer resolution is required to study this complex interplay and dig deeper into the mechanobiology of single cells. Current approaches to measure mechanical properties of adherent cells mainly rely on the exploitation of miniaturized indenters, to poke single cells while measuring the corresponding deformation. This method provides a neat implementation of the everyday approach to measure mechanical properties of a material, but it typically results in a very low throughput and invasive experimental protocol, poorly translatable towards three-dimensional living tissues and biological constructs. To overcome the main limitations of nanoindentation experiments, a radical paradigm change is foreseen, adopting next generation contact-less methods to measure mechanical properties of biological samples with sub-cell resolution. Here we briefly introduce the field of single cell mechanical characterization, and we concentrate on a promising high resolution optical elastography technique, Brillouin spectroscopy. This non-contact technique is rapidly emerging as a potential breakthrough innovation in biomechanics, but the application to single cells is still in its infancy.

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Tumor cell nuclei soften during transendothelial migration

Cited by 52 publications

References 50 publications

Nuclear Stress-Strain State over Micropillars: A Mechanical In silico Study

Nuclear Stress-Strain State over Micropillars: A Mechanical In silico Study

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

Non-contact elastography methods in mechanobiology: a point of view

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