7 results on '"Moutasim KA"'
Search Results
2. Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch
- Author
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Tod, J, Hanley, CJ, Morgan, MR, Rucka, M, Mellows, T, Lopez, M-A, Kiely, P, Moutasim, KA, Frampton, SJ, Sabnis, D, Fine, DR, Johnson, C, Marshall, JF, Scita, G, Jenei, V, and Thomas, GJ
- Abstract
The integrin αvβ6 is upregulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganisation, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis and GTPase activation. Similar to αvβ6, we found that Eps8 was upregulated in >70% of PDAC. In complex with Abi1/Sos1, Eps8 regulated αvβ6-dependent cell migration through activation of Rac1. Downregulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6-dependent TGF-β1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvβ6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-β1 activation (Rho-dependent) functional phenotype respectively.
- Published
- 2017
3. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
- Author
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Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, Noble F, Moutasim KA, King EV, Vijayanand P, Mirnezami AH, Underwood TJ, Ottensmeier CH, and Thomas GJ
- Subjects
- Actins analysis, Adenocarcinoma chemistry, Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Animals, Cancer-Associated Fibroblasts chemistry, Cancer-Associated Fibroblasts physiology, Carcinoma, Non-Small-Cell Lung chemistry, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell chemistry, Carcinoma, Squamous Cell genetics, Cell Count, Cell Transdifferentiation drug effects, Cell Transdifferentiation genetics, Colorectal Neoplasms pathology, Disease Progression, Esophageal Neoplasms chemistry, Esophageal Neoplasms genetics, Female, Head and Neck Neoplasms chemistry, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Humans, Lung Neoplasms chemistry, Lung Neoplasms genetics, Male, Mice, Middle Aged, Mouth Neoplasms pathology, Myofibroblasts chemistry, NADPH Oxidase 4, NADPH Oxidases analysis, NADPH Oxidases genetics, Neoplasm Transplantation, Oropharyngeal Neoplasms pathology, Phenotype, Pyrazoles therapeutic use, Pyrazolones, Pyridines therapeutic use, Pyridones, RNA Interference, Reactive Oxygen Species metabolism, Survival Rate, Up-Regulation, Adenocarcinoma drug therapy, Cancer-Associated Fibroblasts pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Colorectal Neoplasms chemistry, Esophageal Neoplasms drug therapy, Lung Neoplasms drug therapy, Mouth Neoplasms chemistry, Myofibroblasts pathology, NADPH Oxidases antagonists & inhibitors, Oropharyngeal Neoplasms chemistry
- Abstract
Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed., Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided., Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04)., Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types., (© The Author 2017. Published by Oxford University Press.)
- Published
- 2018
- Full Text
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4. Evaluating the effect of immune cells on the outcome of patients with mesothelioma.
- Author
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Chee SJ, Lopez M, Mellows T, Gankande S, Moutasim KA, Harris S, Clarke J, Vijayanand P, Thomas GJ, and Ottensmeier CH
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Mesothelioma pathology, Middle Aged, Neoplasm Staging, Prognosis, Survival Rate, B-Lymphocytes immunology, Killer Cells, Natural immunology, Lymphocytes, Tumor-Infiltrating immunology, Mesothelioma immunology, Mesothelioma mortality, Tumor Microenvironment immunology
- Abstract
Background: We systematically assessed the prognostic and predictive value of infiltrating adaptive and innate immune cells in a large cohort of patients with advanced mesothelioma., Methods: A tissue microarray from 302 samples was constructed. Markers of adaptive immune response in T-cells (CD8
+ , FOXP3+ , CD4+ , CD45RO+ , CD3+ ) and B-cells (CD20+ ), and of innate immune response; neutrophils (NP57+ ), natural killer cells (CD56+ ) and macrophages (CD68+ ) were evaluated., Results: We found that in the epithelioid tumours, high CD4+ and CD20+ counts, and low FOXP3+ , CD68+ and NP57+ counts linked to better outcome. In the non-epithelioid group low CD8+ and low FOXP3+ counts were beneficial.On multivariate analysis low FOXP3+ remained independently associated with survival in both groups. In the epithelioid group additionally high CD4+ , high CD20+ , and low NP57+ counts were prognostic., Conclusions: Our data demonstrate for the first time, in predominately advanced disease, the association of key markers of adaptive and innate immunity with survival and the differential effect of histology. A better understanding of the immunological drivers of the different subtypes of mesothelioma will assist prognostication and disease-specific clinical decision-making.- Published
- 2017
- Full Text
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5. Crowdsourcing for translational research: analysis of biomarker expression using cancer microarrays.
- Author
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Lawson J, Robinson-Vyas RJ, McQuillan JP, Paterson A, Christie S, Kidza-Griffiths M, McDuffus LA, Moutasim KA, Shaw EC, Kiltie AE, Howat WJ, Hanby AM, Thomas GJ, and Smittenaar P
- Subjects
- Data Interpretation, Statistical, Humans, Image Processing, Computer-Assisted methods, Immunohistochemistry, Patient Selection, Biomarkers, Tumor metabolism, Crowdsourcing methods, Neoplasms metabolism, Tissue Array Analysis, Translational Research, Biomedical methods
- Abstract
Background: Academic pathology suffers from an acute and growing lack of workforce resource. This especially impacts on translational elements of clinical trials, which can require detailed analysis of thousands of tissue samples. We tested whether crowdsourcing - enlisting help from the public - is a sufficiently accurate method to score such samples., Methods: We developed a novel online interface to train and test lay participants on cancer detection and immunohistochemistry scoring in tissue microarrays. Lay participants initially performed cancer detection on lung cancer images stained for CD8, and we measured how extending a basic tutorial by annotated example images and feedback-based training affected cancer detection accuracy. We then applied this tutorial to additional cancer types and immunohistochemistry markers - bladder/ki67, lung/EGFR, and oesophageal/CD8 - to establish accuracy compared with experts. Using this optimised tutorial, we then tested lay participants' accuracy on immunohistochemistry scoring of lung/EGFR and bladder/p53 samples., Results: We observed that for cancer detection, annotated example images and feedback-based training both improved accuracy compared with a basic tutorial only. Using this optimised tutorial, we demonstrate highly accurate (>0.90 area under curve) detection of cancer in samples stained with nuclear, cytoplasmic and membrane cell markers. We also observed high Spearman correlations between lay participants and experts for immunohistochemistry scoring (0.91 (0.78, 0.96) and 0.97 (0.91, 0.99) for lung/EGFR and bladder/p53 samples, respectively)., Conclusions: These results establish crowdsourcing as a promising method to screen large data sets for biomarkers in cancer pathology research across a range of cancers and immunohistochemical stains.
- Published
- 2017
- Full Text
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6. Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
- Author
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Mellone M, Hanley CJ, Thirdborough S, Mellows T, Garcia E, Woo J, Tod J, Frampton S, Jenei V, Moutasim KA, Kabir TD, Brennan PA, Venturi G, Ford K, Herranz N, Lim KP, Clarke J, Lambert DW, Prime SS, Underwood TJ, Vijayanand P, Eliceiri KW, Woelk C, King EV, Gil J, Ottensmeier CH, and Thomas GJ
- Subjects
- Animals, Cell Line, Tumor, Extracellular Matrix metabolism, Fibroblasts metabolism, Humans, Mice, Myofibroblasts metabolism, Neoplasms metabolism, Phenotype, Prognosis, Signal Transduction physiology, Transforming Growth Factor beta1 metabolism, Cell Differentiation physiology, Cellular Senescence physiology, Fibroblasts pathology, Myofibroblasts pathology, Neoplasms pathology
- Abstract
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo , showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro , we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
- Published
- 2016
- Full Text
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7. Congenital heart block associated with Sjögren syndrome: case report.
- Author
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Moutasim KA, Shirlaw PJ, Escudier MP, and Poate TW
- Abstract
Background: Congenital heart block is a rare complication of pregnancy associated with Sjögren Syndrome that may result in the death of the foetus or infant, or the need for pacing in the newborn or at a later stage., Case Report: The case is presented of a 64-year-old patient with primary Sjögren Syndrome and a history of having given birth to two sons with congenital heart block, both of whom required pacing several years later., Conclusion: The literature relating to this association is discussed including the suggested mechanism, long-term outcome of mothers of children with congenital heart block and preventive treatment strategies.
- Published
- 2009
- Full Text
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