37 results found
Cortes E, Lachowski D, Rice A, et al., 2018, RAR-β is downregulated in HCC & cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells., Hepatology
Hepatic stellate cells (HSCs) are essential perisinusoidal cells in the healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signalling with cancer cells. Since the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-β) in cirrhotic and HCC patients, as well as the effects of RAR-β activation in HSCs. We found that RAR-β expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid (ATRA) promotes HSC deactivation via RAR-β-dependent transcriptional downregulation of myosin light chain 2 (MLC-2) expression. Furthermore, this also abrogated mechanically driven migration towards stiffer substrates. CONCLUSION: Targeting mechanotransduction in HSCs at the transcriptional level may offer new therapeutic options for a range of liver diseases. This article is protected by copyright. All rights reserved.
Elsharkawy S, Al-Jawad M, Pantano MF, et al., 2018, Protein disorder-order interplay to guide the growth of hierarchical mineralized structures, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Lachowski D, Cortes E, Robinson B, et al., 2018, FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis, FASEB JOURNAL, Vol: 32, Pages: 1099-1107, ISSN: 0892-6638
Matellan C, Del Río Hernández AE, 2018, Cost-effective rapid prototyping and assembly of poly(methyl methacrylate) microfluidic devices., Sci Rep, Vol: 8
The difficulty in translating conventional microfluidics from laboratory prototypes to commercial products has shifted research efforts towards thermoplastic materials for their higher translational potential and amenability to industrial manufacturing. Here, we present an accessible method to fabricate and assemble polymethyl methacrylate (PMMA) microfluidic devices in a "mask-less" and cost-effective manner that can be applied to manufacture a wide range of designs due to its versatility. Laser micromachining offers high flexibility in channel dimensions and morphology by controlling the laser properties, while our two-step surface treatment based on exposure to acetone vapour and low-temperature annealing enables improvement of the surface quality without deformation of the device. Finally, we demonstrate a capillarity-driven adhesive delivery bonding method that can produce an effective seal between PMMA devices and a variety of substrates, including glass, silicon and LiNbO3. We illustrate the potential of this technique with two microfluidic devices, an H-filter and a droplet generator. The technique proposed here offers a low entry barrier for the rapid prototyping of thermoplastic microfluidics, enabling iterative design for laboratories without access to conventional microfabrication equipment.
Samandari M, Juliá MG, Rice A, et al., 2018, Liquid biopsies for management of pancreatic cancer., Transl Res
Pancreatic cancer is one of the main causes of cancer related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, mainly circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management algorithm of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical applications. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
von Erlach TC, Bertazzo S, Wozniak MA, et al., 2018, Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate, NATURE MATERIALS, Vol: 17, Pages: 237-+, ISSN: 1476-1122
Chronopoulos A, Lieberthal TJ, del Río Hernández AE, 2017, Pancreatic cancer: a mechanobiology approach, Convergent Science Physical Oncology, Vol: 3, Pages: 013001-013001
Chronopoulos A, Lieberthal TJ, del Río Hernández AE, 2017, Exosomes as a platform for ‘liquid biopsy’ in pancreatic cancer, Convergent Science Physical Oncology, Vol: 3, Pages: 013005-013005
Inostroza-Brito KE, Collin EC, Majkowska A, et al., 2017, Cross-linking of a biopolymer-peptide co-assembling system, ACTA BIOMATERIALIA, Vol: 58, Pages: 80-89, ISSN: 1742-7061
Lachowski D, Cortes E, Pink D, et al., 2017, Substrate rigidity controls activation and durotaxis in pancreatic stellate cells, Scientific Reports, Vol: 7, ISSN: 2045-2322
Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma, upon activation transitioning to a myofibroblast-like, high matrix secreting phenotype. Given their importance in disease progression, characterisation of PSC activation has been extensive, however one aspect that has been overlooked is the mechano-sensing properties of the cell. Here, through the use of a physiomimetic system that recapitulates the mechanical microenvironment found within healthy and fibrotic pancreas, we demonstrate that matrix stiffness regulates activation and mechanotaxis in PSCs. We show the ability of PSCs to undergo phenotypic transition solely as a result of changes in extracellular matrix stiffness, whilst observing the ability of PSCs to durotactically respond to stiffness variations within their local environment. Our findings implicate the mechanical microenvironment as a potent contributor to PDAC progression and survival via induction of PSC activation and fibrosis, suggesting that direct mechanical reprogramming of PSCs may be a viable alternative in the treatment of this lethal disease.
Rice AJ, Cortes E, Lachowski D, et al., 2017, Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells, Oncogenesis, Vol: 6, Pages: e352-e352, ISSN: 2157-9024
Increased matrix rigidity associated with the fibrotic reaction is documented to stimulate intracellular signalling pathways that promote cancer cell survival and tumour growth. Pancreatic cancer is one of the stiffest of all human solid carcinomas and is characterised by a remarkable desmoplastic reaction. Here we use mouse models, genetically engineered to recapitulate human pancreatic cancer, and several pancreatic cancer cell lines as a model to investigate the effect of matrix stiffness in epithelial-mesenchymal transition (EMT) and resistance to chemotherapeutics. We found that recapitulation of the fibrotic rigidities found in pancreatic cancer tissues promote elements of EMT, including increases in vimentin expression, decreases in E-cadherin expression, nuclear localisation of β-catenin, YAP and TAZ and changes in cell shape towards a mesenchymal phenotype. We also report that stiffness induces chemoresistance to paclitaxel, but not to gemcitabine, both commonly used therapeutics, suggesting that environmental rigidity underlies an aspect of chemoresistance.
Attwood SJ, Cortes E, Haining AWM, et al., 2016, Adhesive ligand tether length affects the size and length of focal adhesions and influences cell spreading and attachment, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
Chronopoulos A, Robinson B, Sarper M, et al., 2016, ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion, NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723
Haining AWM, Lieberthal TJ, Hernandez ADR, 2016, Talin: a mechanosensitive molecule in health and disease, FASEB JOURNAL, Vol: 30, Pages: 2073-2085, ISSN: 0892-6638
Haining AWM, von Essen M, Attwood SJ, et al., 2016, All Subdomains of the Talin Rod Are Mechanically Vulnerable and May Contribute To Cellular Mechanosensing, ACS Nano, Vol: 10, Pages: 6648-6658, ISSN: 1936-0851
Kis Z, Rodin T, Zafar A, et al., 2016, Development of a synthetic gene network to modulate gene expression by mechanical forces, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
Lachowski D, Cortes E, Robinson B, et al., 2016, ELUCIDATING THE BIOMECHANICAL RESPONSE OF HUMAN HEPATIC STELLATE CELLS ON SUBSTRATES MIMICKING HEALTHY AND FIBROTIC MATRIX RIGIDITY, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S706-S706, ISSN: 0168-8278
Robinson BK, Cortes E, Rice AJ, et al., 2016, Quantitative analysis of 3D extracellular matrix remodelling by pancreatic stellate cells, BIOLOGY OPEN, Vol: 5, Pages: 875-882, ISSN: 2046-6390
Sarper M, Cortes E, Lieberthal T, et al., 2016, ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.
Roca-Cusachs P, del Rio A, Puklin-Faucher E, et al., 2013, Integrin-dependent force transmission to the extracellular matrix by alpha-actinin triggers adhesion maturation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E1361-E1370, ISSN: 0027-8424
Roca-Cusachs P, Gauthier NC, del Rio A, et al., 2009, Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 16245-16250, ISSN: 0027-8424
del Rio A, Perez-Jimenez R, Liu R, et al., 2009, Stretching Single Talin Rod Molecules Activates Vinculin Binding, SCIENCE, Vol: 323, Pages: 638-641, ISSN: 0036-8075
Del Rio A, Dutta K, Chavez J, et al., 2007, Solution structure and dynamics of the N-terminal cytosolic domain of rhomboid intramembrane protease from Pseudomonas aeruginosa: Insights into a functional role in intramembrane proteolysis, JOURNAL OF MOLECULAR BIOLOGY, Vol: 365, Pages: 109-122, ISSN: 0022-2836
Del Rio A, Anand A, Ghose R, 2006, Detection of correlated dynamics on multiple timescales by measurement of the differential relaxation of zero- and double-quantum coherences involving sidechain methyl groups in proteins, JOURNAL OF MAGNETIC RESONANCE, Vol: 180, Pages: 1-17, ISSN: 1090-7807
del Rio A, Coto B, Renuncio JAR, et al., 2004, Vapor-liquid equilibria for the binary system 2,2-dimethylbutane plus 1,1-dimethylpropyl methyl ether (TAME) at 298.15, 318.15, and 338.15 K, FLUID PHASE EQUILIBRIA, Vol: 221, Pages: 1-6, ISSN: 0378-3812
Segade L, de Llano JJ, Jimenez E, et al., 2003, Vapor-liquid equilibria of propan-1-ol+1,1-dimethylethyl methyl ether (MTBE) mixtures. Experimental results and modeling, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 5, Pages: 2858-2861, ISSN: 1463-9076
Spuhl O, Arlt W, Hernandez AD, 2003, Prediction of thermodynamic material properties with the COSMO-RS continuum model, Meeting of the GVC Specialized committee on Thermal Dismantling of Gas, Publisher: WILEY-V C H VERLAG GMBH, Pages: 58-62, ISSN: 0009-286X
de Llano JJ, Segade L, Jimenez E, et al., 2003, Vapor-liquid equilibria for the binary system hexan-1-ol plus tert-butyl methyl ether (MTBE) at 298.15, 318.15, and 338.15 K, FLUID PHASE EQUILIBRIA, Vol: 208, Pages: 115-121, ISSN: 0378-3812
del Rio A, Coto B, Pando C, et al., 2002, Vapor-liquid equilibria for the binary system hexane+1,1-dimethylpropyl methyl ether at 298.15, 308.15, 318.15, and 328.15 K, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 41, Pages: 1364-1369, ISSN: 0888-5885
del Rio A, Coto B, Pando C, et al., 2002, Vapor-liquid equilibria and excess properties of octane+1,1-dimethylpropyl methyl ether (TAME) mixtures, FLUID PHASE EQUILIBRIA, Vol: 200, Pages: 41-51, ISSN: 0378-3812
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