Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling

Increased tissue stiffness is a classic characteristic of solid tumors. One of the major contributing factors is increased density of collagen fibers in the extracellular matrix (ECM). Here, we investigate how cancer cells biomechanically interact with and respond to the stiffness of the ECM. Probing the adaptability of cancer cells to altered ECM stiffness using optical tweezers–based microrheology and deformability cytometry, we find that only malignant cancer cells have the ability to adjust to collagen matrices of different densities. Employing microrheology on the biologically relevant spheroid invasion assay, we can furthermore demonstrate that, even within a cluster of cells of similar origin, there are differences in the intracellular biomechanical properties dependent on the cells’ invasive behavior. We reveal a consistent increase of viscosity in cancer cells leading the invasion into the collagen matrices in comparison with cancer cells following in the stalk or remaining in the center of the spheroid. We hypothesize that this differential viscoelasticity might facilitate spheroid tip invasion through a dense matrix. These findings highlight the importance of the biomechanical interplay between cells and their microenvironment for tumor progression.

show abstract

“…Different mechanical cues have been shown to either drive ( Levental et al. , 2009 ) or block ( Ricca et al. , 2018 ) cancer progression.…”

Section: Resultsmentioning

confidence: 99%

Cancer cells’ ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential

Wullkopf

West

Leijnse

et al. 2018

MBoC

204

151

View full text Add to dashboard Cite

show abstract

“…These findings demonstrate that NO production is a mechanistic link between proper architecture and proper function in breast tissues. Please see also the accompanying paper of Ricca et al, 2018 , which describes how the reversion of T4-2 cells induced by a short period of compression in laminin is also mediated by NO production.…”

Section: Discussionmentioning

confidence: 99%

Laminin signals initiate the reciprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs

Furuta

Ren

Mao

et al. 2018

eLife

Self Cite

View full text Add to dashboard Cite

How mammalian tissues maintain their architecture and tissue-specificity is poorly understood. Previously, we documented both the indispensable role of the extracellular matrix (ECM) protein, laminin-111 (LN1), in the formation of normal breast acini, and the phenotypic reversion of cancer cells to acini-like structures in 3-dimensional (3D) gels with inhibitors of oncogenic pathways. Here, we asked how laminin (LN) proteins integrate the signaling pathways necessary for morphogenesis. We report a surprising reciprocal circuitry comprising positive players: laminin-5 (LN5), nitric oxide (NO), p53, HOXD10 and three microRNAs (miRNAs) — that are involved in the formation of mammary acini in 3D. Significantly, cancer cells on either 2-dimensional (2D) or 3D and non-malignant cells on 2D plastic do not produce NO and upregulate negative players: NFκB, EIF5A2, SCA1 and MMP-9 — that disrupt the network. Introducing exogenous NO, LN5 or individual miRNAs to cancer cells reintegrates these pathways and induces phenotypic reversion in 3D. These findings uncover the essential elements of breast epithelial architecture, where the balance between positive- and negative-players leads to homeostasis.

show abstract

“…In many cases, bioengineering tools have played a central role in deciphering mechanotransduction pathways (Polacheck et al, 2013 ; Liu et al, 2017 ). However, there is a growing interest in studying the response of cells from compressive stress in other physiological environments, for example during development (Mammoto and Ingber, 2010 ) and in cancer (Jain et al, 2014 ; Ricca et al, 2018 ). Mechanical forces, such as compression generated by living cells are crucial for the control of embryonic development.…”

Section: Introductionmentioning

confidence: 99%

Advanced Microfluidic Device Designed for Cyclic Compression of Single Adherent Cells

Wang

et al. 2018

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Cells in our body experience different types of stress including compression, tension, and shear. It has been shown that some cells experience permanent plastic deformation after a mechanical tensile load was removed. However, it was unclear whether cells are plastically deformed after repetitive compressive loading and unloading. There have been few tools available to exert cyclic compression at the single cell level. To address technical challenges found in a previous microfluidic compression device, we developed a new single-cell microfluidic compression device that combines an elastomeric membrane block geometry to ensure a flat contact surface and microcontact printing to confine cell spreading within cell trapping chambers. The design of the block geometry inside the compression chamber was optimized by using computational simulations. Additionally, we have implemented step-wise pneumatically controlled cell trapping to allow more compression chambers to be incorporated while minimizing mechanical perturbation on trapped cells. Using breast epithelial MCF10A cells stably expressing a fluorescent actin marker, we successfully demonstrated the new device design by separately trapping single cells in different chambers, confining cell spreading on microcontact printed islands, and applying cyclic planar compression onto single cells. We found that there is no permanent deformation after a 0.5 Hz cyclic compressive load for 6 min was removed. Overall, the development of the single-cell compression microfluidic device opens up new opportunities in mechanobiology and cell mechanics studies.

show abstract

Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling

Cited by 33 publications

References 72 publications

Cancer cells’ ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential

Cancer cells’ ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential

Laminin signals initiate the reciprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs

Advanced Microfluidic Device Designed for Cyclic Compression of Single Adherent Cells

Contact Info

Product

Resources

About