scholarly journals Nature of active forces in tissues: how contractile cells can form extensile monolayers

2020 ◽  
Author(s):  
Lakshmi Balasubramaniam ◽  
Amin Doostmohammadi ◽  
Thuan Beng Saw ◽  
Gautham Hari Narayana Sankara Narayana ◽  
Romain Mueller ◽  
...  
Keyword(s):  
Cancer Progression ◽  
General Mechanism ◽  
Cell Competition ◽  
Cell Monolayers ◽  
Adhesion Sites ◽  
Contractile System ◽  
Cell Substrate ◽  
Transcription Factor Activation ◽  
In Silico Modeling ◽  
Pulling Forces

Actomyosin machinery endows cells with contractility at a single cell level. However, at a tissue scale, cells can show either contractile or extensile behaviour based on the direction of pushing or pulling forces due to neighbour interactions or substrate interactions. Previous studies have shown that a monolayer of fibroblasts behaves as a contractile system1 while a monolayer of epithelial cells2,3 or neural crest cells behaves as an extensile system.4 How these two contradictory sources of force generation can coexist has remained unexplained. Through a combination of experiments using MDCK (Madin Darby Canine Kidney) cells, and in-silico modeling, we uncover the mechanism behind this switch in behaviour of epithelial cell monolayers from extensile to contractile as the weakening of intercellular contacts. We find that this switch in active behaviour also promotes the buildup of tension at the cell-substrate interface through an increase in actin stress fibers and higher traction forces. This in turn triggers a mechanotransductive response in vinculin translocation to focal adhesion sites and YAP (Yes-associated protein) transcription factor activation. Our studies also show that differences in extensility and contractility act to sort cells, thus determining a general mechanism for mechanobiological pattern formation during cell competition, morphogenesis and cancer progression.

scholarly journals Cell Fitness: More Than Push-Ups

2021 ◽  
Vol 22 (2) ◽  
pp. 518
Author(s):  
Adam James Ferrari ◽  
Ronny Drapkin ◽  
Rajan Gogna
Keyword(s):  
Cancer Progression ◽  
Hippo Pathway ◽  
Cancer Therapeutics ◽  
Protein Isoforms ◽  
Cell Junction ◽  
Cell Competition ◽  
Molecular Features ◽  
Oncogenic Pathways ◽  
Diagnostic Potential ◽  
The Impact

Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three recent studies that expand our understanding of the molecular features governing CC. In particular, we will focus on a molecular fitness fingerprint, oncogenic pathways, and the importance of cell junction stability. A fitness fingerprint, mediated by flower (hFWE) protein isoforms, dictates that cells expressing the flower-win isoforms will outcompete adjacent flower-loss-expressing cells. The impact of the flower protein isoforms is seen in cancer progression and may have diagnostic potential. The yes-associated protein (YAP) and TAZ transcription factors, central mediators of the oncogenic Hippo pathway, elevate peritumoral fitness thereby protecting against tumor progression and provide a suppressive barrier. Similarly, COL17A1 is a key component in hemidesmosome stability, and its expression in epidermal stem cells contributes to fitness competition and aging characteristics. The contributions of these pathways to disease development and progression will help define how CC is hijacked to favor cancer growth. Understanding these features will also help frame the diagnostic and therapeutic possibilities that may place CC in the crosshairs of cancer therapeutics.

scholarly journals In silico mechanobiochemical modeling of morphogenesis in cell monolayers

2017 ◽  
Author(s):  
Bahador Marzban ◽  
Xiao Ma ◽  
Xiaoliang Qing ◽  
Hongyan Yuan
Keyword(s):  
Computational Model ◽  
Reaction Diffusion ◽  
Cell Interaction ◽  
Cell Polarization ◽  
Cell Morphogenesis ◽  
Cell Monolayers ◽  
Irregular Shapes ◽  
Cell Substrate ◽  
Living Tissues

Cell morphogenesis is a fundamental process involved in tissue formation. One of the challenges in the fabrication of living tissues in vitro is to recapitulate the complex morphologies of individual cells. Despite tremendous progress in understanding biophysical principles underlying tissue/organ morphogenesis at the organ level, little work has been done to understand morphogenesis at the cellular and microtissue level. In this work, we developed a 2D computational model for studying cell morphogenesis in monolayer tissues. The model is mainly composed of four modules: mechanics of cytoskeleton, cell motility, cell-substrate interaction, and cell-cell interaction. The model integrates the biochemical and mechanical activities within individual cells spatiotemporally. Finite element method (FEM) is used to model the irregular shapes of cells and to solve the resulting system of reaction-diffusion-stress equations. Automated mesh generation is used to handle the element distortion in FEM due to the large shape changes of the cells. The computer program can simulate tens to hundreds of cells interacting with each other and with the elastic substrate on desktop workstations efficiently. The simulations demonstrated that our computational model can be used to study cell polarization, single cell migration, durotaxis, and morphogenesis in cell monolayers.

scholarly journals Hypoxia-inducible factor (HIF): fuel for cancer progression

2021 ◽  
Vol 14 ◽  
Author(s):  
Saurabh Satija ◽  
Harpreet Kaur ◽  
Murtaza M. Tambuwala ◽  
Prabal Sharma ◽  
Manish Vyas ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Activation ◽  
Underlying Mechanisms ◽  
Adaptive Reactions

Hypoxia is an integral part of tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mchanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

Quantification of Cell-Substrate Adhesion Area and Cell Shape Distributions in MCF7 Cell Monolayers

10.3791/61461 ◽  
2020 ◽  
Author(s):  
Maciej Wakula ◽  
Anna Balcerak ◽  
Urszula Smietanka ◽  
Mateusz Chmielarczyk ◽  
Ryszard Konopiński ◽  
...  
Keyword(s):  
Cell Shape ◽  
Mcf7 Cell ◽  
Cell Monolayers ◽  
Substrate Adhesion ◽  
Cell Substrate ◽  
Cell Substrate Adhesion

scholarly journals Actin flow and talin dynamics govern rigidity sensing in actin–integrin linkage through talin extension

2014 ◽  
Vol 11 (99) ◽  
pp. 20140734 ◽  
Author(s):  
Hiroaki Hirata ◽  
Keng-Hwee Chiam ◽  
Chwee Teck Lim ◽  
Masahiro Sokabe
Keyword(s):  
Actin Filaments ◽  
Substrate Stiffness ◽  
Mechanical Stiffness ◽  
Adhesion Sites ◽  
Substrate Adhesion ◽  
Rigidity Sensing ◽  
Cell Substrate ◽  
Simple Physical Model ◽  
Biophysical Mechanism ◽  
Cell Substrate Adhesion

At cell–substrate adhesion sites, the linkage between actin filaments and integrin is regulated by mechanical stiffness of the substrate. Of potential molecular regulators, the linker proteins talin and vinculin are of particular interest because mechanical extension of talin induces vinculin binding with talin, which reinforces the actin–integrin linkage. For understanding the molecular and biophysical mechanism of rigidity sensing at cell–substrate adhesion sites, we constructed a simple physical model to examine a role of talin extension in the stiffness-dependent regulation of actin–integrin linkage. We show that talin molecules linking between retrograding actin filaments and substrate-bound integrin are extended in a manner dependent on substrate stiffness. The model predicts that, in adhesion complexes containing ≈30 talin links, talin is extended enough for vinculin binding when the substrate is stiffer than 1 kPa. The lifetime of talin links needs to be 2–5 s to achieve an appropriate response of talin extension against substrate stiffness. Furthermore, changes in actin velocity drastically shift the range of substrate stiffness that induces talin–vinculin binding. Our results suggest that talin extension is a key step in sensing and responding to substrate stiffness at cell adhesion sites.

ADHESION OF TUMOR CELLS TO EXTRACELLULAR MATRIX IS MEDIATED BY FIBRONECTIN

1987 ◽  
Author(s):  
L Almirall ◽  
J Aznar-Salatti ◽  
I Calopa ◽  
A Ordinas ◽  
E Bastida
Keyword(s):  
Extracellular Matrix ◽  
Binding Sites ◽  
Vessel Wall ◽  
Cell Binding ◽  
Cell Monolayers ◽  
Adhesion Sites ◽  
Bacteria Adhesion ◽  
Adhesive Site ◽  
Adhesion Site

Tumor cell (TC) vessel wall adhesion is thougth to occur at specific sites of exposed extracellular matrix (ECM).To determine the role of fibronectin (FN) in TC/ECM adhesion,we measured; 1)TC adhesion to intact cultured endothelial cell monolayers (EC) or their ECMs,with or without incubation with a polyclonal antibody (Ab) to human FN, or a monoclonal antibody (Mab) to the cell binding site of FN (3E3);2)TC adhesion to EC or their exposed ECMs incubated with specific peptides against bacteria adhesion sites (I 133-79) or the peptide GRGDSP contained in the cell binding sites of several adhesive proteins.TC adhesion was measured as number of 111In-labeled A-549 adenocarcinoma cellsxlO /disc. ECMs were exposed by removing the ECs with N2 flow or EGTA treatment.There was 5.5±1x10 A-549/ EC covered disc (Table). Treatment of ECs with the Abs or peptides had no effect on TC adhesion.TC adhesion to the two ECM preparation were 42 ± 12 and 55±10 respectively.(Table).Blockage of the FN adhesive site by either Ab inhibited TC adhesion (p < 0.01). In contrast,blockage of the bacteria-adhesion site or incubation with GRGDSP had not significant effects in TC adhesion. The table shows the results (mearv±SEM (* p < 0.01).We conclude that TC adhesion to ECM but not to ECs,is dependent upon FN.

Stretchable electrical cell-substrate impedance sensor platform for monitoring cell monolayers under strain

2021 ◽  
Vol 336 ◽  
pp. 129656
Author(s):  
Chen Zhou ◽  
Sebastian Bette ◽  
Aaron Babendreyer ◽  
Christina Hoffmann ◽  
Sven Gerlach ◽  
...  
Keyword(s):  
Cell Monolayers ◽  
Cell Substrate ◽  
Sensor Platform ◽  
Impedance Sensor

scholarly journals Mechanisms of cell competition: Themes and variations

2013 ◽  
Vol 200 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Romain Levayer ◽  
Eduardo Moreno
Keyword(s):  
Drosophila Melanogaster ◽  
Error Correction ◽  
Cancer Progression ◽  
Short Range ◽  
Cell Competition ◽  
Dividing Cells ◽  
Bona Fide ◽  
Growing Population

Cell competition is the short-range elimination of slow-dividing cells through apoptosis when confronted with a faster growing population. It is based on the comparison of relative cell fitness between neighboring cells and is a striking example of tissue adaptability that could play a central role in developmental error correction and cancer progression in both Drosophila melanogaster and mammals. Cell competition has led to the discovery of multiple pathways that affect cell fitness and drive cell elimination. The diversity of these pathways could reflect unrelated phenomena, yet recent evidence suggests some common wiring and the existence of a bona fide fitness comparison pathway.

scholarly journals Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members.

1994 ◽  
Vol 125 (6) ◽  
pp. 1371-1384 ◽  
Author(s):  
K Takeuchi ◽  
N Sato ◽  
H Kasahara ◽  
N Funayama ◽  
A Nagafuchi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Plasma Membranes ◽  
Family Members ◽  
Initial Step ◽  
Functional Interaction ◽  
Adhesion Sites ◽  
Substrate Adhesion ◽  
Cell Substrate ◽  
Cell Substrate Adhesion ◽  
Cell Cell

To examine the functions of ERM family members (ezrin, radixin, and moesin), mouse epithelial cells (MTD-1A cells) and thymoma cells (L5178Y), which coexpress all of them, were cultured in the presence of antisense phosphorothioate oligonucleotides (PONs) complementary to ERM sequences. Immunoblotting revealed that the antisense PONs selectively suppressed the expression of each member. Immunofluorescence microscopy of these ezrin, radixin, or moesin "single-suppressed" MTD-1A cells revealed that the ERM family members are colocalized at cell-cell adhesion sites, microvilli, and cleavage furrows, where actin filaments are densely associated with plasma membranes. The ezrin/radixin/moesin antisense PONs mixture induced the destruction of both cell-cell and cell-substrate adhesion, as well as the disappearance of microvilli. Ezrin or radixin antisense PONs individually affected the initial step of the formation of both cell-cell and cell-substrate adhesion, but did not affect the microvilli structures. In sharp contrast, moesin antisense PONs did not singly affect cell-cell and cell-substrate adhesion, whereas it partly affected the microvilli structures. These data indicate that ezrin and radixin can be functionally substituted, that moesin has some synergetic functional interaction with ezrin and radixin, and that these ERM family members are involved in cell-cell and cell-substrate adhesion, as well as microvilli formation.

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