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Mechanosensitive Ion Channels: TRPV4 and P2X7 in Disseminating Cancer Cells.
Hope JM, Greenlee JD, King MR
(2018) Cancer J 24: 84-92
MeSH Terms: Animals, Cell Movement, Humans, Mechanotransduction, Cellular, Neoplasms, Receptors, Purinergic P2X7, TRPV Cation Channels
Show Abstract · Added April 15, 2019
Cancer metastasis is the second leading cause of death in the United States. Despite its morbidity, metastasis is an inefficient process that few cells can survive. However, cancer cells can overcome these metastatic barriers via cellular responses to microenvironmental cues, such as through mechanotransduction. This review focuses on the mechanosensitive ion channels TRPV4 and P2X7, and their roles in metastasis, as both channels have been shown to significantly affect tumor cell dissemination. Upon activation, these channels help form tumor neovasculature, promote transendothelial migration, and increase cell motility. Conversely, they have also been linked to forms of cancer cell death dependent upon levels of activation, implying the complex functionality of mechanosensitive ion channels. Understanding the roles of TRPV4, P2X7 and other mechanosensitive ion channels in these processes may reveal new possible drug targets that modify channel function to reduce a tumor's metastatic potential.
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MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
The nature and biology of basement membranes.
Pozzi A, Yurchenco PD, Iozzo RV
(2017) Matrix Biol 57-58: 1-11
MeSH Terms: Agrin, Animals, Basement Membrane, Bone Diseases, Developmental, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Gene Expression Regulation, Heparan Sulfate Proteoglycans, Humans, Laminin, Lupus Nephritis, Mechanotransduction, Cellular, Membrane Glycoproteins, Mutation, Protein Isoforms
Show Abstract · Added March 26, 2017
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Copyright © 2017 Elsevier B.V. All rights reserved.
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16 MeSH Terms
The Mechanics of Single Cell and Collective Migration of Tumor Cells.
Lintz M, Muñoz A, Reinhart-King CA
(2017) J Biomech Eng 139:
MeSH Terms: Animals, Cell Movement, Computer Simulation, Extracellular Matrix, Humans, Mechanotransduction, Cellular, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis
Show Abstract · Added April 10, 2019
Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.
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MeSH Terms
Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension.
Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q, Zhao J, Tai Y, Tang Y, Zhang YY, Rehman S, Sugahara M, Qi Z, Gorcsan J, Vargas SO, Saggar R, Saggar R, Wallace WD, Ross DJ, Haley KJ, Waxman AB, Parikh VN, De Marco T, Hsue PY, Morris A, Simon MA, Norris KA, Gaggioli C, Loscalzo J, Fessel J, Chan SY
(2016) J Clin Invest 126: 3313-35
MeSH Terms: Adolescent, Adult, Aged, Animals, Child, Collagen, Endothelial Cells, Extracellular Matrix, Female, Glutamic Acid, Humans, Hypertension, Pulmonary, Infant, Intracellular Signaling Peptides and Proteins, Male, Mechanotransduction, Cellular, Middle Aged, Myocytes, Smooth Muscle, Phosphoproteins, Rats, Rats, Sprague-Dawley, Vascular Stiffness, Young Adult
Show Abstract · Added September 16, 2016
Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.
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23 MeSH Terms
Regulation of invadopodia by mechanical signaling.
Parekh A, Weaver AM
(2016) Exp Cell Res 343: 89-95
MeSH Terms: Extracellular Matrix, Humans, Mechanotransduction, Cellular, Models, Biological, Podosomes, Tumor Microenvironment
Show Abstract · Added February 15, 2016
Mechanical rigidity in the tumor microenvironment is associated with a high risk of tumor formation and aggressiveness. Adhesion-based signaling driven by a rigid microenvironment is thought to facilitate invasion and migration of cancer cells away from primary tumors. Proteolytic degradation of extracellular matrix (ECM) is a key component of this process and is mediated by subcellular actin-rich structures known as invadopodia. Both ECM rigidity and cellular traction stresses promote invadopodia formation and activity, suggesting a role for these structures in mechanosensing. The presence and activity of mechanosensitive adhesive and signaling components at invadopodia further indicates the potential for these structures to utilize myosin-dependent forces to probe and remodel their ECM environments. Here, we provide a brief review of the role of adhesion-based mechanical signaling in controlling invadopodia and invasive cancer behavior.
Copyright © 2015 Elsevier Inc. All rights reserved.
2 Communities
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6 MeSH Terms
Tagging strategies strongly affect the fate of overexpressed caveolin-1.
Han B, Tiwari A, Kenworthy AK
(2015) Traffic 16: 417-38
MeSH Terms: Animals, COS Cells, Caveolin 1, Caveolin 2, Cell Line, Cell Line, Tumor, Cell Membrane, Cercopithecus aethiops, Endocytosis, Green Fluorescent Proteins, HeLa Cells, Humans, Luminescent Proteins, Mechanotransduction, Cellular, Proto-Oncogene Proteins c-myc
Show Abstract · Added February 13, 2015
Caveolin-1 (Cav1) is the primary scaffolding protein of caveolae, flask-shaped invaginations of the plasma membrane thought to function in endocytosis, mechanotransduction, signaling and lipid homeostasis. A significant amount of our current knowledge about caveolins and caveolae is derived from studies of transiently overexpressed, C-terminally tagged caveolin proteins. However, how different tags affect the behavior of ectopically expressed Cav1 is still largely unknown. To address this question, we performed a comparative analysis of the subcellular distribution, oligomerization state and detergent resistance of transiently overexpressed Cav1 labeled with three different C-terminal tags (EGFP, mCherry and myc). We show that addition of fluorescent protein tags enhances the aggregation and/or degradation of both wild-type Cav1 and an oligomerization defective P132L mutant. Strikingly, complexes formed by overexpressed Cav1 fusion proteins excluded endogenous Cav1 and Cav2, and the properties of native caveolins were largely preserved even when abnormal aggregates were present in cells. These findings suggest that differences in tagging strategies may be a source of variation in previously published studies of Cav1 and that overexpressed Cav1 may exert functional effects outside of caveolae. They also highlight the need for a critical re-evaluation of current knowledge based on transient overexpression of tagged Cav1.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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15 MeSH Terms
Primary cilia signaling mediates intraocular pressure sensation.
Luo N, Conwell MD, Chen X, Kettenhofen CI, Westlake CJ, Cantor LB, Wells CD, Weinreb RN, Corson TW, Spandau DF, Joos KM, Iomini C, Obukhov AG, Sun Y
(2014) Proc Natl Acad Sci U S A 111: 12871-6
MeSH Terms: Animals, Cadaver, Child, Cilia, Humans, Intraocular Pressure, Male, Mechanotransduction, Cellular, Mice, Mice, Inbred C57BL, Mice, Knockout, Oculocerebrorenal Syndrome, Phosphoric Monoester Hydrolases, Sensation, TRPV Cation Channels, Trabecular Meshwork, Transforming Growth Factor beta, Tumor Necrosis Factor-alpha
Show Abstract · Added March 19, 2018
Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.
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18 MeSH Terms
A contractile and counterbalancing adhesion system controls the 3D shape of crawling cells.
Burnette DT, Shao L, Ott C, Pasapera AM, Fischer RS, Baird MA, Der Loughian C, Delanoe-Ayari H, Paszek MJ, Davidson MW, Betzig E, Lippincott-Schwartz J
(2014) J Cell Biol 205: 83-96
MeSH Terms: Actin Cytoskeleton, Actinin, Actins, Animals, COS Cells, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Shape, Cercopithecus aethiops, Focal Adhesions, Humans, Mechanotransduction, Cellular, Models, Biological, Nonmuscle Myosin Type IIA, Pressure, Time Factors, Transfection
Show Abstract · Added August 25, 2017
How adherent and contractile systems coordinate to promote cell shape changes is unclear. Here, we define a counterbalanced adhesion/contraction model for cell shape control. Live-cell microscopy data showed a crucial role for a contractile meshwork at the top of the cell, which is composed of actin arcs and myosin IIA filaments. The contractile actin meshwork is organized like muscle sarcomeres, with repeating myosin II filaments separated by the actin bundling protein α-actinin, and is mechanically coupled to noncontractile dorsal actin fibers that run from top to bottom in the cell. When the meshwork contracts, it pulls the dorsal fibers away from the substrate. This pulling force is counterbalanced by the dorsal fibers' attachment to focal adhesions, causing the fibers to bend downward and flattening the cell. This model is likely to be relevant for understanding how cells configure themselves to complex surfaces, protrude into tight spaces, and generate three-dimensional forces on the growth substrate under both healthy and diseased conditions.
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18 MeSH Terms
Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells.
Sewell-Loftin MK, DeLaughter DM, Peacock JR, Brown CB, Baldwin HS, Barnett JV, Merryman WD
(2014) Biomaterials 35: 2809-15
MeSH Terms: Animals, Cell Proliferation, Chickens, Collagen Type I, Cross-Linking Reagents, Endocardium, Epithelial-Mesenchymal Transition, Hyaluronic Acid, Mechanotransduction, Cellular, Methacrylates, Myocardial Contraction, Signal Transduction, Tissue Scaffolds
Show Abstract · Added May 27, 2014
Epithelial-to-mesenchymal transition (EMT) of endocardial cells is a critical initial step in the formation of heart valves. The collagen gel in vitro model has provided significant information on the role of growth factors regulating EMT but has not permitted investigation of mechanical factors. Therefore we sought to develop a system to probe the effects of mechanical inputs on endocardial EMT by incorporating hyaluronic acid (HA), the primary component of endocardial cushions in developing heart valves, into the gel assay. This was achieved using a combination collagen and crosslinkable methacrylated HA hydrogel (Coll-MeHA). Avian atrioventricular canal explants on Coll-MeHA gels showed increased numbers of transformed cells. Analysis of the mechanical properties of Coll-MeHA gels shows that stiffness does not directly affect EMT. Hydrogel deformation from the beating myocardium of explants directly led to higher levels of regional gel deformation and larger average strain magnitudes associated with invaded cells on Coll-MeHA gels. Inhibition of this contraction reduced EMT on all gel types, although to a lesser extent on Coll-MeHA gels. Using the system we have developed, which permits the manipulation of mechanical factors, we have demonstrated that active mechanical forces play a role in the regulation of endocardial EMT.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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13 MeSH Terms