46 results found
Lachowski D, Cortes E, Rice A, et al., 2019, Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis, Scientific Reports, Vol: 9
Perone Y, Farrugia AJ, Meira AR, et al., 2019, SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer., Nat Commun, Vol: 10
Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
Matellan C, Del Río Hernández AE, 2019, Engineering the cellular mechanical microenvironment - from bulk mechanics to the nanoscale., J Cell Sci, Vol: 132
The field of mechanobiology studies how mechanical properties of the extracellular matrix (ECM), such as stiffness, and other mechanical stimuli regulate cell behaviour. Recent advancements in the field and the development of novel biomaterials and nanofabrication techniques have enabled researchers to recapitulate the mechanical properties of the microenvironment with an increasing degree of complexity on more biologically relevant dimensions and time scales. In this Review, we discuss different strategies to engineer substrates that mimic the mechanical properties of the ECM and outline how these substrates have been applied to gain further insight into the biomechanical interaction between the cell and its microenvironment.
Cortes E, Lachowski D, Rice A, et al., 2019, Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor, ONCOGENE, Vol: 38, Pages: 2910-2922, ISSN: 0950-9232
Cortes E, Lachowski D, Robinson B, et al., 2019, Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival, EMBO REPORTS, Vol: 20, ISSN: 1469-221X
Cortes E, Sarper M, Robinson B, et al., 2019, GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment, EMBO REPORTS, Vol: 20, ISSN: 1469-221X
Yeldag G, Rice A, Hernandez ADR, 2018, Chemoresistance and the Self-Maintaining Tumor Microenvironment, CANCERS, Vol: 10, ISSN: 2072-6694
Samandari M, Julia MG, Rice A, et al., 2018, Liquid biopsies for management of pancreatic cancer, TRANSLATIONAL RESEARCH, Vol: 201, Pages: 98-127, ISSN: 1931-5244
Walker C, Mojares E, del Río Hernández A, 2018, Role of Extracellular Matrix in Development and Cancer Progression, International Journal of Molecular Sciences, Vol: 19, Pages: 3028-3028
<jats:p>The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM’s composition and organization are spatiotemporally regulated to control cell behaviour and differentiation, but dysregulation of ECM dynamics leads to the development of diseases such as cancer. The chemical cues presented by the ECM have been appreciated as key drivers for both development and cancer progression. However, the mechanical forces present due to the ECM have been largely ignored but recently recognized to play critical roles in disease progression and malignant cell behaviour. Here, we review the ways in which biophysical forces of the microenvironment influence biochemical regulation and cell phenotype during key stages of human development and cancer progression.</jats:p>
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, ISSN: 0270-9139
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.
Haining AWM, Rahikainen R, Cortes E, et al., 2018, Mechanotransduction in talin through the interaction of the R8 domain with DLC1, PLOS BIOLOGY, Vol: 16, ISSN: 1545-7885
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
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.
Mykuliak V, Haining A, von Essen M, et al., Mechanical unfolding reveals stable 3-helix intermediates in talin and α-catenin, PLoS Computational Biology, ISSN: 1553-734X
Mechanical stability is a key feature in the regulation of structural scaffolding proteins and their functions. Despite the abundance of α-helical structures among the human proteome and their undisputed importance in health and disease, the fundamental principles of their behavior under mechanical load are poorly understood. Talin and α-catenin are two key molecules in focal adhesions and adherensjunctions, respectively. In this study, we used a combination of atomistic steered molecular dynamics (SMD) simulations, polyprotein engineering, and single-molecule ManuscriptClick here to download Manuscriptmanuscript_text_30032018.docx2atomic force microscopy (smAFM) to investigate unfolding of theseproteins. SMD simulations revealed that talin rod α-helix bundles as well as α-catenin α-helix domains unfold through stable 3-helix intermediates. While the 5-helix bundles were found to be mechanically stable, a second stable conformation corresponding to the 3-helix state was revealed. Mechanically weaker 4-helix bundles easily unfolded into a stable 3-helix conformation. The results of smAFM experiments were in agreement with the findings of the computational simulations. The disulfide clamp mutants, (resistant to mechanical unfolding) designed to protect the stable state, support the 3-helix intermediate model in both experimental and computational setups. As a result, multiplediscrete unfolding intermediate states in the talin and α-catenin unfolding pathway were discovered. Better understanding of the mechanical unfolding mechanism of α-helix proteins is a keysteptowards comprehensive models describing the mechanoregulationof proteins.
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
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
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
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.
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.
Chronopoulos A, Lieberthal TJ, Hernandez AEDR, 2017, Exosomes as a platform for 'liquid biopsy' in pancreatic cancer, CONVERGENT SCIENCE PHYSICAL ONCOLOGY, Vol: 3, ISSN: 2057-1739
Chronopoulos A, Lieberthal TJ, Hernandez AEDR, 2017, Pancreatic cancer: a mechanobiology approach, CONVERGENT SCIENCE PHYSICAL ONCOLOGY, Vol: 3, ISSN: 2057-1739
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
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
Sarper M, Lieberthal T, Del Rio Hernandez AE, Elucidating the Effect of Extracellular Matrix Remodeling by Stromal Cells on Pancreatic Cancer Cell Invasion in 3D Organotypic Systems, Jove-Journal of Visualized Experiments, ISSN: 1940-087X
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
Sarper M, Cortes E, Lieberthal TJ, et al., 2016, ATRA modulates mechanical activation of TGF-beta by pancreatic stellate cells, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
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
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
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