Modulating cancer cell mechanics and actin cytoskeleton structure by chemical and mechanical stimulations

Azadi, Shohreh; Tafazzoli-Shadpour, Mohammad; Soleimani, Masoud; Warkiani, Majid Ebrahimi

doi:10.1002/jbm.a.36670

Cited by 28 publications

(21 citation statements)

References 40 publications

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“…A similar work on breast cancer cells using matrices of different rigidity discovered a direct correlation between migration capacity and increase of matrix stiffness (83). Moreover, cells treated with cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, had an increased elastic modulus followed by a decrease in migration ability.…”

Section: Regulation Of Cancer Resistance Through Cellular Stiffnessmentioning

confidence: 94%

“…Moreover, cells treated with cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, had an increased elastic modulus followed by a decrease in migration ability. Here, the authors explained that cell mechanics are not only regulated by mechanical cues of the ECM but also by biochemical signals mediated through membrane receptors, such as EGFR (83).…”

Section: Regulation Of Cancer Resistance Through Cellular Stiffnessmentioning

confidence: 99%

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The Extracellular, Cellular, and Nuclear Stiffness, a Trinity in the Cancer Resistome—A Review

Deville

Cordes

2019

Front. Oncol.

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Alterations in mechano-physiological properties of a tissue instigate cancer burdens in parallel to common genetic and epigenetic alterations. The chronological and mechanistic interrelation between the various extra- and intracellular aspects remains largely elusive. Mechano-physiologically, integrins and other cell adhesion molecules present the main mediators for transferring and distributing forces between cells and the extracellular matrix (ECM). These cues are channeled via focal adhesion proteins, termed the focal adhesomes, to cytoskeleton and nucleus and vice versa thereby affecting the pathophysiology of multicellular cancer tissues. In combination with simultaneous activation of diverse downstream signaling pathways, the phenotypes of cancer cells are created and driven characterized by deregulated transcriptional and biochemical cues that elicit the hallmarks of cancer. It, however, remains unclear how elastostatic modifications, i.e., stiffness, in the extracellular, intracellular, and nuclear compartment contribute and control the resistance of cancer cells to therapy. In this review, we discuss how stiffness of unique tumor components dictates therapy response and what is known about the underlying molecular mechanisms.

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Section: Regulation Of Cancer Resistance Through Cellular Stiffnessmentioning

confidence: 94%

Section: Regulation Of Cancer Resistance Through Cellular Stiffnessmentioning

confidence: 99%

The Extracellular, Cellular, and Nuclear Stiffness, a Trinity in the Cancer Resistome—A Review

Deville

Cordes

2019

Front. Oncol.

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“…More recently, hypoxia has been shown to alter cancer cell force generation through RhoA- 1 6 ROCK signaling (7). Other essential factors in the tumor microenvironment such as epidermal growth factors have been shown to modulate cancer cell mechanotype including local cell elasticity, actin cytoskeleton architecture, and cell migration (12). It will be interesting in future work to define the interplay among multiple signals that activate RhoA-ROCK (57) to regulate cancer cell behaviors in the complex tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…Mechanical cues, such as increased matrix stiffness in tumors, cause cancer cells to increase their stiffness and force production (8)(9)(10). While various soluble and mechanical cues are known to regulate cancer cell mechanotype (11,12), our knowledge of the shared molecular mediators that regulate cellular mechanotype and functional behaviors to drive metastasis is still emerging.…”

Section: Introductionmentioning

confidence: 99%

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Kim

Vazquez-Hidalgo

Abdou

et al. 2019

Preprint

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The ability of cells to deform and generate forces are key mechanical properties that are implicated in metastasis. While various soluble and mechanical cues are known to regulate cancer cell mechanical phenotype or mechanotype, our knowledge of how cells translate external signals into changes in mechanotype is still emerging. We previously discovered that activation of β -adrenergic signaling, which results from soluble stress hormone cues, causes cancer cells to be stiffer or less deformable; this stiffer mechanotype was associated with increased cell motility and invasion. Here, we characterize how β -adrenergic activation is translated into changes in cellular mechanotype by identifying molecular mediators that regulate key components of mechanotype including cellular deformability, traction forces, and nonmuscle myosin II (NMII) activity. Using a micropillar assay and computational modelling, we determine that β AR activation increases cellular force generation by increasing the number of actin-myosin binding events; this mechanism is distinct from how cells increase force production in response to matrix stiffness, suggesting that cells regulate their mechanotype using a complementary mechanism in response to stress hormone cues. To identify the molecules that modulate cellular mechanotype with β AR activation, we use a high throughput filtration platform to screen the effects of pharmacologic and genetic perturbations on β AR regulation of whole cell deformability. Our results indicate that β AR activation decreases cancer cell deformability and increases invasion by signaling through RhoA, ROCK, and NMII. Our findings establish β AR-RhoA-ROCK-NMII as a primary signaling axis that mediates cancer cell mechanotype, which provides a foundation for future interventions to stop metastasis.

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“…Mechanical signals from the surrounding environment play a vital role in regulating tumor cell behavior (Chaudhuri et al, 2018; Emon et al, 2018). Specifically, in vitro studies have shown that tumor cell migration and motility are strongly affected by the substrate mechanics (Azadi, Tafazzoli‐Shadpour, et al, 2019; van Helvert et al, 2018). Significant efforts have been spent on investigating the alteration of tumor cell structural and biological behavior in response to the rigidity of the cellular substrate such as change in cell morphology, adhesion, stiffness, protein expression, migration, and motility (Azadi, Tafazzoli‐Shadpour, et al, 2019; Jiwlawat et al, 2019; Pandamooz et al, 2020; Rice et al, 2017a; Shukla et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Characterizing the effect of substrate stiffness on the extravasation potential of breast cancer cells using a 3D microfluidic model

Azadi

Tafazzoli-Shadpour

Warkiani

2020

Biotech & Bioengineering

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Different biochemical and biomechanical cues from tumor microenvironment affect the extravasation of cancer cells to distant organs; among them, the mechanical signals are poorly understood. Although the effect of substrate stiffness on the primary migration of cancer cells has been previously probed, its role in regulating the extravasation ability of cancer cells is still vague. Herein, we used a microfluidic device to mimic the extravasation of tumor cells in a 3D microenvironment containing cancer cells, endothelial cells, and the biological matrix. The microfluidic‐based extravasation model was utilized to probe the effect of substrate stiffness on the invasion ability of breast cancer cells. MCF7 and MDA‐MB‐231 cancer cells were cultured among substrates with different stiffness which followed by monitoring their extravasation capability through the microfluidic device. Our results demonstrated that acidic collagen at a concentration of 2.5 mg/ml promotes migration of cancer cells. Additionally, the substrate softening resulted in up to 46% reduction in the invasion of breast cancer cells. The substrate softening not only affected the number of extravasated cells but also reduced their migration distance up to 53%. We further investigated the secreted level of matrix metalloproteinase 9 (MMP9) and identified that there is a positive correlation between substrate stiffening, MMP9 concentration, and extravasation of cancer cells. These findings suggest that the substrate stiffness mediates the cancer cells extravasation in a microfluidic model. Changes in MMP9 level could be one of the possible underlying mechanisms which need more investigations to be addressed thoroughly.

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Modulating cancer cell mechanics and actin cytoskeleton structure by chemical and mechanical stimulations

Cited by 28 publications

References 40 publications

The Extracellular, Cellular, and Nuclear Stiffness, a Trinity in the Cancer Resistome—A Review

The Extracellular, Cellular, and Nuclear Stiffness, a Trinity in the Cancer Resistome—A Review

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Characterizing the effect of substrate stiffness on the extravasation potential of breast cancer cells using a 3D microfluidic model

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