The Role of Microenvironmental Cues and Mechanical Loading Milieus in Breast Cancer Cell Progression and Metastasis

Riehl, Brandon D.; Kim, Eunju; Bouzid, Tasneem; Lim, Jung Yul

doi:10.3389/fbioe.2020.608526

Cited by 23 publications

(27 citation statements)

References 114 publications

(144 reference statements)

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“…Moreover, the stiffness of the cellular microenvironment is known to affect the cells' mechanical properties and behavior, and an increase in the stiffness has been linked to many diseases. Most notably, in tumor formation and cancer progression, the ECM stiffness increases [11,15,34,[50][51][52], affecting how mechanical strains are transmitted between the cells. Tightly packed epithelial monolayers on deformable substrates form an excellent platform for studying how forces propagate between cells and what is the effect of the substrate stiffness in this process.…”

Section: Discussionmentioning

confidence: 99%

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The effect of substrate stiffness on tensile force transduction in the epithelial monolayers

Tervonen

Korpela

Nymark

et al. 2021

Preprint

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In recent years, the importance of mechanical signaling and the cellular mechanical microenvironment in affecting cellular behavior has been widely accepted. Cells in epithelial monolayers are mechanically connected to each other and the underlying extracellular matrix (ECM), forming a highly connected mechanical system subjected to various mechanical cues from their environment, such as the ECM stiffness. Changes in the ECM stiffness have been linked to many pathologies, including tumor formation. However, our understanding of how ECM stiffness and its heterogeneities affect the transduction of mechanical forces in epithelial monolayers is lacking. To investigate this, we used a combination of experimental and computational methods. The experiments were conducted using epithelial cells cultured on an elastic substrate and applying a mechanical stimulus by moving a single cell by micromanipulation. To replicate our experiments computationally and quantify the forces transduced in the epithelium, we developed a new model that described the mechanics of both the cells and the substrate. Our model further enabled the simulations with local stiffness heterogeneities. We found the substrate stiffness to distinctly affect the force transduction as well as the cellular movement and deformation following an external force. Also, we found that local changes in the stiffness can alter the cells' response to external forces over long distances. Our results suggest that this long-range signaling of the substrate stiffness depends on the cells' ability to resist deformation. Furthermore, we found that the cell's elasticity in the apico-basal direction provides a level of detachment between the apical cell-cell junctions and the basal focal adhesions. Our simulation results show potential for increased ECM stiffness, e.g. due to a tumor, to modulate mechanical signaling between cells also outside the stiff region. Furthermore, the developed model provides a good platform for future studies on the interactions between epithelial monolayers and elastic substrates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The effect of substrate stiffness on tensile force transduction in the epithelial monolayers

Tervonen

Korpela

Nymark

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The simplicity, low cost, and reproducibility of 2D models made them the mainstay of biological research, but in vivo tissue complexity can only be approached using 3D systems. In fact, in tridimensional systems, the mechanical properties can be tuned so that models mimic a wide range of tissue stiffness [30][31][32]. Moreover, cell adhesion, spreading, and migration is not constrained to a single layer [33][34][35]; sequestration/gradients of soluble biomolecules can be modulated to finely control cell fate and differentiation [36,37]; and ECM can be customized to reproduce the in vivo cell experience through different sets of chemical and mechanical signals [38][39][40].…”

Section: Mechanomodeling: Inclusion Of Biophysical Signals In 3d Cancer Systemsmentioning

confidence: 99%

“…the mechanical properties can be tuned so that models mimic a wide range of tissue stiffness [30][31][32]. Moreover, cell adhesion, spreading, and migration is not constrained to a single layer [33][34][35]; sequestration/gradients of soluble biomolecules can be modulated to finely control cell fate and differentiation [36,37]; and ECM can be customized to reproduce the in vivo cell experience through different sets of chemical and mechanical signals [38][39][40].…”

Section: Mechanomodeling: Inclusion Of Biophysical Signals In 3d Cancer Systemsmentioning

confidence: 99%

Mechanical Studies of the Third Dimension in Cancer: From 2D to 3D Model

Paradiso

Serpelloni

Francis

et al. 2021

IJMS

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From the development of self-aggregating, scaffold-free multicellular spheroids to the inclusion of scaffold systems, 3D models have progressively increased in complexity to better mimic native tissues. The inclusion of a third dimension in cancer models allows researchers to zoom out from a significant but limited cancer cell research approach to a wider investigation of the tumor microenvironment. This model can include multiple cell types and many elements from the extracellular matrix (ECM), which provides mechanical support for the tissue, mediates cell-microenvironment interactions, and plays a key role in cancer cell invasion. Both biochemical and biophysical signals from the extracellular space strongly influence cell fate, the epigenetic landscape, and gene expression. Specifically, a detailed mechanistic understanding of tumor cell-ECM interactions, especially during cancer invasion, is lacking. In this review, we focus on the latest achievements in the study of ECM biomechanics and mechanosensing in cancer on 3D scaffold-based and scaffold-free models, focusing on each platform’s level of complexity, up-to-date mechanical tests performed, limitations, and potential for further improvements.

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“…The ECM provides physical and biochemical cues for cellular proliferation and migration ( 10 ). Such interactions influence their behavior and consequently activates different signaling pathways ( 11 , 12 ). Factors to consider when engineering physical microenvironments include matrix elasticity, topography, flow within the system and substrate chemistry ( Figure 1 ).…”

Section: Role Of the Physical Microenvironment As A Driver Of Bone Metastasismentioning

confidence: 99%

Embracing Mechanobiology in Next Generation Organ-On-A-Chip Models of Bone Metastasis

Slay

Meldrum

Amer

2021

Front. Med. Technol.

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Bone metastasis in breast cancer is associated with high mortality. Biomechanical cues presented by the extracellular matrix play a vital role in driving cancer metastasis. The lack of in vitro models that recapitulate the mechanical aspects of the in vivo microenvironment hinders the development of novel targeted therapies. Organ-on-a-chip (OOAC) platforms have recently emerged as a new generation of in vitro models that can mimic cell-cell interactions, enable control over fluid flow and allow the introduction of mechanical cues. Biomaterials used within OOAC platforms can determine the physical microenvironment that cells reside in and affect their behavior, adhesion, and localization. Refining the design of OOAC platforms to recreate microenvironmental regulation of metastasis and probe cell-matrix interactions will advance our understanding of breast cancer metastasis and support the development of next-generation metastasis-on-a-chip platforms. In this mini-review, we discuss the role of mechanobiology on the behavior of breast cancer and bone-residing cells, summarize the current capabilities of OOAC platforms for modeling breast cancer metastasis to bone, and highlight design opportunities offered by the incorporation of mechanobiological cues in these platforms.

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The Role of Microenvironmental Cues and Mechanical Loading Milieus in Breast Cancer Cell Progression and Metastasis

Cited by 23 publications

References 114 publications

The effect of substrate stiffness on tensile force transduction in the epithelial monolayers

The effect of substrate stiffness on tensile force transduction in the epithelial monolayers

Mechanical Studies of the Third Dimension in Cancer: From 2D to 3D Model

Embracing Mechanobiology in Next Generation Organ-On-A-Chip Models of Bone Metastasis

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