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ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice.
Kimura Y, Fukuda A, Ogawa S, Maruno T, Takada Y, Tsuda M, Hiramatsu Y, Araki O, Nagao M, Yoshikawa T, Ikuta K, Yoshioka T, Wang Z, Akiyama H, Wright CV, Takaori K, Uemoto S, Chiba T, Seno H
(2018) Gastroenterology 155: 194-209.e2
MeSH Terms: Adenocarcinoma in Situ, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Culture Techniques, Cell Differentiation, DNA-Binding Proteins, Mice, Nuclear Proteins, Pancreatic Ducts, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor
Show Abstract · Added April 3, 2018
BACKGROUND & AIMS - The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice.
METHODS - We performed studies with Ptf1a-Cre;Kras mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;Kras;Arid1a mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;Kras; Brg1mice). Pancreatic ductal cells (PDCs) were isolated from Arid1a mice and from Arid1a;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry.
RESULTS - Ptf1a-Cre;Kras mice developed PanINs, whereas Ptf1a-Cre;Kras;Arid1a mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6.
CONCLUSIONS - ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
1 Members
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13 MeSH Terms
Shear stress induces noncanonical autophagy in intestinal epithelial monolayers.
Kim SW, Ehrman J, Ahn MR, Kondo J, Lopez AAM, Oh YS, Kim XH, Crawley SW, Goldenring JR, Tyska MJ, Rericha EC, Lau KS
(2017) Mol Biol Cell 28: 3043-3056
MeSH Terms: Actins, Autophagy, Caco-2 Cells, Cell Culture Techniques, Epithelium, Humans, Intestinal Mucosa, Intestines, Microvilli, Stress, Physiological, Vacuoles
Show Abstract · Added April 3, 2018
Flow of fluids through the gut, such as milk from a neonatal diet, generates a shear stress on the unilaminar epithelium lining the lumen. We report that exposure to physiological levels of fluid shear stress leads to the formation of large vacuoles, containing extracellular contents within polarizing intestinal epithelial cell monolayers. These observations lead to two questions: how can cells lacking primary cilia transduce shear stress, and what molecular pathways support the formation of vacuoles that can exceed 80% of the cell volume? We find that shear forces are sensed by actin-rich microvilli that eventually generate the apical brush border, providing evidence that these structures possess mechanosensing ability. Importantly, we identified the molecular pathway that regulates large vacuole formation downstream from mechanostimulation to involve central components of the autophagy pathway, including ATG5 and LC3, but not Beclin. Together our results establish a novel link between the actin-rich microvilli, the macroscopic transport of fluids across cells, and the noncanonical autophagy pathway in organized epithelial monolayers.
© 2017 Kim et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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MeSH Terms
Epidermal growth factor receptor inhibition downregulates -induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.
Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM, Gobert AP, Wilson KT
(2018) Gut 67: 1247-1260
MeSH Terms: Animals, Antineoplastic Agents, Cell Culture Techniques, Epithelial Cells, ErbB Receptors, Gastritis, Gefitinib, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Quinazolines, Stomach Neoplasms
Show Abstract · Added June 29, 2017
OBJECTIVE - Gastric cancer is the third leading cause of cancer death worldwide and infection by is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.
DESIGN - We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of ( mice) were also used.
RESULTS - In C57BL/6 mice, gefitinib decreased and expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected versus control mice. In -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked ri-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from versus mice. Epithelial EGFR activation persisted in humans and mice after eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.
CONCLUSIONS - These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in -infected individuals.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
0 Communities
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14 MeSH Terms
Clustering of integrin α5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells.
Starchenko A, Graves-Deal R, Yang YP, Li C, Zent R, Singh B, Coffey RJ
(2017) Mol Biol Cell 28: 1288-1300
MeSH Terms: Antibodies, Cadherins, Cell Adhesion, Cell Culture Techniques, Cell Line, Tumor, Cell Polarity, Colorectal Neoplasms, Epithelial Cells, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5, Integrin alpha5beta1, Integrin beta1, Membrane Proteins, Membranes
Show Abstract · Added May 3, 2017
Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer. Integrin-mediated contact with the extracellular matrix defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity. Role(s) for lateral integrins in this polarization process and the consequences of their disruption are incompletely understood. We show that addition of an integrin β1-activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. P4G11 induces clustering of integrin α5β1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin α5β1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin α5 abrogates the epithelial-organizing effects of P4G11. In addition, polymerization of fibronectin is required for the effects of P4G11, and addition of polymerized superfibronectin is sufficient to induce tight junction formation and apicobasolateral polarization. In the normal human colon, we show that integrin α5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin α5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin α5β1 in regulating epithelial morphogenesis.
© 2017 Starchenko et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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16 MeSH Terms
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer.
Li C, Singh B, Graves-Deal R, Ma H, Starchenko A, Fry WH, Lu Y, Wang Y, Bogatcheva G, Khan MP, Milne GL, Zhao S, Ayers GD, Li N, Hu H, Washington MK, Yeatman TJ, McDonald OG, Liu Q, Coffey RJ
(2017) Proc Natl Acad Sci U S A 114: E2852-E2861
MeSH Terms: Animals, Antineoplastic Agents, Immunological, Cell Culture Techniques, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms, Crizotinib, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Hydroxyprostaglandin Dehydrogenases, Mice, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyridines, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Tissue Array Analysis, Versicans, Xenograft Model Antitumor Assays
Show Abstract · Added May 3, 2017
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFR-neutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most up-regulated genes in CC was the tumor suppressor , and the most up-regulated gene in SC was () in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.
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3 Members
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22 MeSH Terms
Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype.
Carey SP, Martin KE, Reinhart-King CA
(2017) Sci Rep 7: 42088
MeSH Terms: Cell Culture Techniques, Cell Movement, Collagen, Epithelial Cells, Extracellular Matrix, Humans, Models, Biological, Phenotype, Tumor Microenvironment
Show Abstract · Added April 10, 2019
A critical step in breast cancer progression is local tissue invasion, during which cells pass from the epithelial compartment to the stromal compartment. We recently showed that malignant leader cells can promote the invasion of otherwise non-invasive epithelial follower cells, but the effects of this induced-invasion phenomenon on follower cell phenotype remain unclear. Notably, this process can expose epithelial cells to the stromal extracellular matrix (ECM), which is distinct from the ECM within the normal epithelial microenvironment. Here, we used a 3D epithelial morphogenesis model in which cells were cultured in biochemically and mechanically defined matrices to examine matrix-mediated gene expression and the associated phenotypic response. We found that 3D collagen matrix promoted expression of mesenchymal genes including MT1-MMP, which was required for collagen-stimulated invasive behavior. Epithelial invasion required matrix anchorage as well as signaling through Src, PI3K, and Rac1, and increasingly stiff collagen promoted dispersive epithelial cell invasion. These results suggest that leader cell-facilitated access to the stromal ECM may trigger an invasive phenotype in follower epithelial cells that could enable them to actively participate in local tissue invasion.
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Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration.
Aamodt KI, Aramandla R, Brown JJ, Fiaschi-Taesch N, Wang P, Stewart AF, Brissova M, Powers AC
(2016) Am J Physiol Endocrinol Metab 311: E859-E868
MeSH Terms: Activins, Adenosine, Adenosine A2 Receptor Agonists, Adenosine-5'-(N-ethylcarboxamide), Adult, Automation, Cell Culture Techniques, Cell Proliferation, Drug Evaluation, Preclinical, Erythropoietin, Exenatide, Female, GABA Agents, Harmine, Humans, Incretins, Insulin-Secreting Cells, Male, Middle Aged, Monoamine Oxidase Inhibitors, Myostatin, Nucleosides, Peptides, Platelet-Derived Growth Factor, Prolactin, Regeneration, Serotonin, Serotonin Receptor Agonists, Vasodilator Agents, Venoms, Young Adult, gamma-Aminobutyric Acid
Show Abstract · Added April 26, 2017
Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers. β-Cells from each donor were assessed for their function and ability to enter the cell cycle by cotransduction with adenoviruses encoding cell cycle regulators cdk6 and cyclin D3. Using this approach, we tested 12 previously identified mitogens, including neurotransmitters, hormones, growth factors, and molecules, involved in adenosine and Tgf-1β signaling. Each compound was tested in a wide concentration range either in the presence of basal (5 mM) or high (11 mM) glucose. Treatment with the control compound harmine, a Dyrk1a inhibitor, led to a significant increase in Ki-67 β-cells, whereas treatment with other compounds had limited to no effect on human β-cell proliferation. This new scalable approach reduces the time and effort required for sensitive and specific evaluation of human β-cell proliferation, thus allowing for increased testing of candidate human β-cell mitogens.
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2 Members
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32 MeSH Terms
3D Printing of Tissue Engineered Constructs for In Vitro Modeling of Disease Progression and Drug Screening.
Vanderburgh J, Sterling JA, Guelcher SA
(2017) Ann Biomed Eng 45: 164-179
MeSH Terms: Animals, Cell Culture Techniques, Drug Evaluation, Preclinical, Humans, Models, Biological, Printing, Three-Dimensional, Tissue Engineering
Show Abstract · Added April 26, 2017
2D cell culture and preclinical animal models have traditionally been implemented for investigating the underlying cellular mechanisms of human disease progression. However, the increasing significance of 3D vs. 2D cell culture has initiated a new era in cell culture research in which 3D in vitro models are emerging as a bridge between traditional 2D cell culture and in vivo animal models. Additive manufacturing (AM, also known as 3D printing), defined as the layer-by-layer fabrication of parts directed by digital information from a 3D computer-aided design file, offers the advantages of simultaneous rapid prototyping and biofunctionalization as well as the precise placement of cells and extracellular matrix with high resolution. In this review, we highlight recent advances in 3D printing of tissue engineered constructs that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs.
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2 Members
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7 MeSH Terms
Differential responses of induced pluripotent stem cell-derived cardiomyocytes to anisotropic strain depends on disease status.
Chun YW, Voyles DE, Rath R, Hofmeister LH, Boire TC, Wilcox H, Lee JH, Bellan LM, Hong CC, Sung HJ
(2015) J Biomech 48: 3890-6
MeSH Terms: Biomarkers, Cardiac Myosins, Cardiomyopathy, Dilated, Cell Culture Techniques, Cell Differentiation, Extracellular Matrix, Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac, Myosin Light Chains, Sarcomeres, Stress, Mechanical, Troponin T
Show Abstract · Added October 21, 2015
Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs׳ responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150 kPa at 5% anisotropic cyclic strain and 1 Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study. When iPSC-CMs were exposed to three strain conditions (no strain, 5% static strain, and 5% cyclic strain), the static strain elicited significant induction of sarcomere components in comparison to other strain conditions. However, this induction occurred only in iPSC-CMs from a healthy volunteer ("control iPSC-CMs"), not in iPSC-CMs from the DCM patient ("DCM iPSC-CMs"). The donor type also significantly influenced gene expressions of cell-cell and cell-matrix interaction markers in response to the strain conditions. Gene expression of connexin-43 (cell-cell interaction) had a higher fold change in healthy versus diseased iPSC-CMs under static and cyclic strain, as opposed to integrins α-5 and α-10 (cell-matrix interaction). In summary, our iPSC-CM-based study to model the effects of different strain conditions suggests that intrinsic, genetic-based differences in the cardiomyocyte responses to strain may influence disease manifestation in vivo.
Copyright © 2015 Elsevier Ltd. All rights reserved.
1 Communities
1 Members
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13 MeSH Terms
A single-islet microplate assay to measure mouse and human islet insulin secretion.
Truchan NA, Brar HK, Gallagher SJ, Neuman JC, Kimple ME
(2015) Islets 7: e1076607
MeSH Terms: Adult, Animals, Biological Assay, Cell Culture Techniques, Female, Glucose, Humans, Insulin, Insulin Secretion, Islets of Langerhans, Male, Mice, Middle Aged, Young Adult
Show Abstract · Added August 2, 2016
One complication to comparing β-cell function among islet preparations, whether from genetically identical or diverse animals or human organ donors, is the number of islets required per assay. Islet numbers can be limiting, meaning that fewer conditions can be tested; other islet measurements must be excluded; or islets must be pooled from multiple animals/donors for each experiment. Furthermore, pooling islets negates the possibility of performing single-islet comparisons. Our aim was to validate a 96-well plate-based single islet insulin secretion assay that would be as robust as previously published methods to quantify glucose-stimulated insulin secretion from mouse and human islets. First, we tested our new assay using mouse islets, showing robust stimulation of insulin secretion 24 or 48 h after islet isolation. Next, we utilized the assay to quantify mouse islet function on an individual islet basis, measurements that would not be possible with the standard pooled islet assay methods. Next, we validated our new assay using human islets obtained from the Integrated Islet Distribution Program (IIDP). Human islets are known to have widely varying insulin secretion capacity, and using our new assay we reveal biologically relevant factors that are significantly correlated with human islet function, whether displayed as maximal insulin secretion response or fold-stimulation of insulin secretion. Overall, our results suggest this new microplate assay will be a useful tool for many laboratories, expert or not in islet techniques, to be able to precisely quantify islet insulin secretion from their models of interest.
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14 MeSH Terms