31 results found
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.
Lachowski D, Cortes E, Robinson B, et al., 2017, FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis., FASEB J
Focal adhesion kinase (FAK) is a key molecule in focal adhesions and regulates fundamental processes in cells such as growth, survival, and migration. FAK is one of the first molecules recruited to focal adhesions in response to external mechanical stimuli and therefore is a pivotal mediator of cell mechanosignaling, and relays these stimuli to other mechanotransducers within the cytoplasm. Yes-associated protein (YAP) has been identified recently as one of these core mechanotransducers. YAP translocates to the nucleus following changes in cell mechanics to promote the expression of genes implicated in motility, apoptosis, proliferation, and organ growth. Here, we show that FAK controls the nuclear translocation and activation of YAP in response to mechanical activation and submit that the YAP-dependent process of durotaxis requires a cell with an asymmetric distribution of active and inactive FAK molecules.-Lachowski, D., Cortes, E., Robinson, B., Rice, A., Rombouts, K., Del Río Hernández, A. E. FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis.
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
del Rio A, Coto B, Pando C, et al., 2001, Vapor-liquid equilibria and excess properties of cyclohexane-1,1-dimethylpropyl methyl ether (TAME) mixtures, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 40, Pages: 689-695, ISSN: 0888-5885
del Rio A, Coto B, Pando C, et al., 2001, Vapor-liquid equilibria for the binary systems decane+1, 1-dimethylethyl methyl ether (MTBE) and decane+1, 1-dimethylpropyl methyl ether (TAME) at 308.15, 318.15 and 328.15 K, FLUID PHASE EQUILIBRIA, Vol: 187, Pages: 299-310, ISSN: 0378-3812
del Rio A, Horstmann S, Renuncio JAR, et al., 2001, Isothermal vapor-liquid equilibrium and excess enthalpy data for the binary systems methyl tert-butyl ether plus cyclohexane and ethyl tert-butyl ether plus cyclohexane, n-hexane, and n-heptane in a temperature range from 298.15 to 393.15 K, JOURNAL OF CHEMICAL AND ENGINEERING DATA, Vol: 46, Pages: 1181-1187, ISSN: 0021-9568
del Rio A, Coto R, Pando C, et al., 1999, Vapour-liquid equilibria for the binary system cyclohexane-1,1-dimethylethyl methyl ether (MTBE) at 298.15, 308.15 and 318.15 K, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 1, Pages: 4995-4998, ISSN: 1463-9076
Robinson B, Rice A, Cortes E, et al., Assessment of extracellular matrix remodeling using 3D Matrigel/collagen matrices and second harmonic generation microscopy, Jove-Journal of Visualized Experiments, ISSN: 1940-087X
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