Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure

Purkayastha, Purboja; Jaiswal, Manish K.; Lele, Tanmay P.

doi:10.1002/cm.21680

Cited by 22 publications

(13 citation statements)

References 106 publications

(120 reference statements)

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“…We first asked whether the effects of long-term mechanical compression on collective cell migration depended on the invasive potential of cells. Solid compressive stress ranges from 0.1 to 10 kPa have been reported in human tumors and 0.25–8 kPa in murine tumors ( Purkayastha et al, 2021 ). To address this, we conducted wound healing assays of non-tumorigenic (MCF10A) and cancer (4T1) breast epithelial cells subjected to different levels of compressive stress.…”

Section: Resultsmentioning

confidence: 99%

Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

Cai

Nguyen

Bashirzadeh

et al. 2022

Front. Cell Dev. Biol.

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Cellular unjamming is the collective fluidization of cell motion and has been linked to many biological processes, including development, wound repair, and tumor growth. In tumor growth, the uncontrolled proliferation of cancer cells in a confined space generates mechanical compressive stress. However, because multiple cellular and molecular mechanisms may be operating simultaneously, the role of compressive stress in unjamming transitions during cancer progression remains unknown. Here, we investigate which mechanism dominates in a dense, mechanically stressed monolayer. We find that long-term mechanical compression triggers cell arrest in benign epithelial cells and enhances cancer cell migration in transitions correlated with cell shape, leading us to examine the contributions of cell–cell adhesion and substrate traction in unjamming transitions. We show that cadherin-mediated cell–cell adhesion regulates differential cellular responses to compressive stress and is an important driver of unjamming in stressed monolayers. Importantly, compressive stress does not induce the epithelial–mesenchymal transition in unjammed cells. Furthermore, traction force microscopy reveals the attenuation of traction stresses in compressed cells within the bulk monolayer regardless of cell type and motility. As traction within the bulk monolayer decreases with compressive pressure, cancer cells at the leading edge of the cell layer exhibit sustained traction under compression. Together, strengthened intercellular adhesion and attenuation of traction forces within the bulk cell sheet under compression lead to fluidization of the cell layer and may impact collective cell motion in tumor development and breast cancer progression.

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Section: Resultsmentioning

confidence: 99%

Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

Cai

Nguyen

Bashirzadeh

et al. 2022

Front. Cell Dev. Biol.

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“…Altered ECM synthesis by CAFs and cancer cells results in a fibrotic process termed desmoplasia, in which overshooting collagen production by fibroblast results in a rigid meshwork of type I collagen-rich fibrils. By adhering to them, myofibroblastic CAFs set this meshwork under strong tension and cause an increased interstitial pressure typical of solid tumors [ 434 , 435 ]. Conversely, ECM-cleaving MMPs, typically found during wound healing and in fibrotic processes, determine the turnover of the tumor stroma and reduce contact guidance by fibrillar matrix structures [ 436 ].…”

Section: Mmps and Tme: More Than A Hit-and-run Relationmentioning

confidence: 99%

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

Niland

Riscanevo

Eble

2021

IJMS

225

107

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Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell–matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.

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“…Morphological changes in nuclear structure, such as increased nuclear size, irregular shape by grooving, convolutions and invaginations of the nuclear envelope and altered organization by disturbed chromatin distribution, are commonly used cancer markers by pathologists [ 15 ]. Mechanical compression through confinement aid in mechanical adaptation of the cell as shown with Hela-Kyoto cancer cells in which stretching of the nuclear envelope and upregulation of actomyosin contractility were observed [ 16 , 17 ]. Furthermore, irregular nuclear morphology of cancer cells aligns with altered expression of nuclear envelope proteins such as lamins A/C or lamin B in cancers as detailed by Denais et al ., which has the capacity to promote metastatic processes [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Application of sequential cyclic compression on cancer cells in a flexible microdevice

2023

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Mechanical forces shape physiological structure and function within cell and tissue microenvironments, during which cells strive to restore their shape or develop an adaptive mechanism to maintain cell integrity depending on strength and type of the mechanical loading. While some cells are shown to experience permanent plastic deformation after a repetitive mechanical tensile loading and unloading, the impact of such repetitive compression on deformation of cells is yet to be understood. As such, the ability to apply cyclic compression is crucial for any experimental setup aimed at the study of mechanical compression taking place in cell and tissue microenvironments. Here, we demonstrate such cyclic compression using a microfluidic compression platform on live cell actin in SKOV-3 ovarian cancer cells. Live imaging of the actin cytoskeleton dynamics of the compressed cells was performed for varying pressures applied sequentially in ascending order during cell compression. Additionally, recovery of the compressed cells was investigated by capturing actin cytoskeleton and nuclei profiles of the cells at zero time and 24 h-recovery after compression in end point assays. This was performed for a range of mild pressures within the physiological range. Results showed that the phenotypical response of compressed cells during recovery after compression with 20.8 kPa differed observably from that for 15.6 kPa. This demonstrated the ability of the platform to aid in the capture of differences in cell behaviour as a result of being compressed at various pressures in physiologically relevant manner. Differences observed between compressed cells fixed at zero time or after 24 h-recovery suggest that SKOV-3 cells exhibit deformations at the time of the compression, a proposed mechanism cells use to prevent mechanical damage. Thus, biomechanical responses of SKOV-3 ovarian cancer cells to sequential cyclic compression and during recovery after compression could be revealed in a flexible microdevice. As demonstrated in this work, the observation of morphological, cytoskeletal and nuclear differences in compressed and non-compressed cells, with controlled micro-scale mechanical cell compression and recovery and using live-cell imaging, fluorescent tagging and end point assays, can give insights into the mechanics of cancer cells.

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Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure

Cited by 22 publications

References 106 publications

Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

Application of sequential cyclic compression on cancer cells in a flexible microdevice

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