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Results: 1 to 10 of 532

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Novel three-dimensional cultures provide insights into thyroid cancer behavior.
Lee MA, Bergdorf KN, Phifer CJ, Jones CY, Byon SY, Sawyer LM, Bauer JA, Weiss VL
(2020) Endocr Relat Cancer 27: 111-121
MeSH Terms: Actin Cytoskeleton, Antineoplastic Agents, Apoptosis, Cell Culture Techniques, Cell Movement, Cell Proliferation, High-Throughput Screening Assays, Humans, Imidazoles, Oximes, Spheroids, Cellular, Thyroid Neoplasms, Tumor Cells, Cultured
Show Abstract · Added March 3, 2020
Thyroid cancer has the fastest growing incidence of any cancer in the United States, as measured by the number of new cases per year. Despite advances in tissue culture techniques, a robust model for thyroid cancer spheroid culture is yet to be developed. Using eight established thyroid cancer cell lines, we created an efficient and cost-effective 3D culture system that can enhance our understanding of in vivo treatment response. We found that all eight cell lines readily form spheroids in culture with unique morphology, size, and cytoskeletal organization. In addition, we developed a high-throughput workflow that allows for drug screening of spheroids. Using this approach, we found that spheroids from K1 and TPC1 cells demonstrate significant differences in their sensitivities to dabrafenib treatment that closely model expected patient drug response. In addition, K1 spheroids have increased sensitivity to dabrafenib when compared to monolayer K1 cultures. Utilizing traditional 2D cultures of these cell lines, we evaluated the mechanisms of this drug response, showing dramatic and acute changes in their actin cytoskeleton as well as inhibition of migratory behavior in response to dabrafenib treatment. Our study is the first to describe the development of a robust spheroid system from established cultured thyroid cancer cell lines and adaptation to a high-throughput format. We show that combining 3D culture with traditional 2D methods provides a complementary and powerful approach to uncover drug sensitivity and mechanisms of inhibition in thyroid cancer.
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13 MeSH Terms
Energetic regulation of coordinated leader-follower dynamics during collective invasion of breast cancer cells.
Zhang J, Goliwas KF, Wang W, Taufalele PV, Bordeleau F, Reinhart-King CA
(2019) Proc Natl Acad Sci U S A 116: 7867-7872
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Energy Metabolism, Female, Glucose, Humans, Intracellular Space, Neoplasm Invasiveness
Show Abstract · Added April 10, 2019
The ability of primary tumor cells to invade into adjacent tissues, followed by the formation of local or distant metastasis, is a lethal hallmark of cancer. Recently, locomoting clusters of tumor cells have been identified in numerous cancers and associated with increased invasiveness and metastatic potential. However, how the collective behaviors of cancer cells are coordinated and their contribution to cancer invasion remain unclear. Here we show that collective invasion of breast cancer cells is regulated by the energetic statuses of leader and follower cells. Using a combination of in vitro spheroid and ex vivo organoid invasion models, we found that cancer cells dynamically rearrange leader and follower positions during collective invasion. Cancer cells invade cooperatively in denser collagen matrices by accelerating leader-follower switching thus decreasing leader cell lifetime. Leader cells exhibit higher glucose uptake than follower cells. Moreover, their energy levels, as revealed by the intracellular ATP/ADP ratio, must exceed a threshold to invade. Forward invasion of the leader cell gradually depletes its available energy, eventually leading to leader-follower transition. Our computational model based on intracellular energy homeostasis successfully recapitulated the dependence of leader cell lifetime on collagen density. Experiments further supported model predictions that decreasing the cellular energy level by glucose starvation decreases leader cell lifetime whereas increasing the cellular energy level by AMP-activated kinase (AMPK) activation does the opposite. These findings highlight coordinated invasion and its metabolic regulation as potential therapeutic targets of cancer.
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11 MeSH Terms
p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate.
Nyeng P, Heilmann S, Löf-Öhlin ZM, Pettersson NF, Hermann FM, Reynolds AB, Semb H
(2019) Dev Cell 49: 31-47.e9
MeSH Terms: Animals, Body Patterning, Cadherins, Catenins, Cell Differentiation, Cell Lineage, Cell Movement, Embryonic Development, Flow Cytometry, Gene Expression Regulation, Developmental, Humans, Islets of Langerhans, Mice, Pancreas, Pancreatic Ducts, Receptors, Notch, Signal Transduction, Stem Cells
Show Abstract · Added March 29, 2019
The mechanism of how organ shape emerges and specifies cell fate is not understood. Pancreatic duct and endocrine lineages arise in a spatially distinct domain from the acinar lineage. Whether these lineages are pre-determined or settle once these niches have been established remains unknown. Here, we reconcile these two apparently opposing models, demonstrating that pancreatic progenitors re-localize to establish the niche that will determine their ultimate fate. We identify a p120ctn-regulated mechanism for coordination of organ architecture and cellular fate mediated by differential E-cadherin based cell sorting. Reduced p120ctn expression is necessary and sufficient to re-localize a subset of progenitors to the peripheral tip domain, where they acquire an acinar fate. The same mechanism is used re-iteratively during endocrine specification, where it balances the choice between the alpha and beta cell fates. In conclusion, organ patterning is regulated by p120ctn-mediated cellular positioning, which precedes and determines pancreatic progenitor fate.
Copyright © 2019 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Myosin IIA drives membrane bleb retraction.
Taneja N, Burnette DT
(2019) Mol Biol Cell 30: 1051-1059
MeSH Terms: Actins, Animals, Blister, COS Cells, Cell Membrane, Cell Membrane Structures, Cell Movement, Cell Surface Extensions, Chlorocebus aethiops, Cytokinesis, Cytoplasm, Cytoskeletal Proteins, HeLa Cells, Humans, Myosin Type II, Nerve Tissue Proteins, Nonmuscle Myosin Type IIA, Nonmuscle Myosin Type IIB
Show Abstract · Added March 27, 2019
Membrane blebs are specialized cellular protrusions that play diverse roles in processes such as cell division and cell migration. Blebbing can be divided into three distinct phases: bleb nucleation, bleb growth, and bleb retraction. Following nucleation and bleb growth, the actin cortex, comprising actin, cross-linking proteins, and nonmuscle myosin II (MII), begins to reassemble on the membrane. MII then drives the final phase, bleb retraction, which results in reintegration of the bleb into the cellular cortex. There are three MII paralogues with distinct biophysical properties expressed in mammalian cells: MIIA, MIIB, and MIIC. Here we show that MIIA specifically drives bleb retraction during cytokinesis. The motor domain and regulation of the nonhelical tailpiece of MIIA both contribute to its ability to drive bleb retraction. These experiments have also revealed a relationship between faster turnover of MIIA at the cortex and its ability to drive bleb retraction.
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18 MeSH Terms
Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.
von Lersner A, Droesen L, Zijlstra A
(2019) Clin Exp Metastasis 36: 87-95
MeSH Terms: Activated-Leukocyte Cell Adhesion Molecule, Animals, Cell Adhesion, Cell Movement, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Invasiveness, Neoplasms
Show Abstract · Added April 10, 2019
In epithelial-derived cancers, altered regulation of cell-cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with conventional organization of five Ig-like domains involved in homo- and heterotypic adhesions. Like many IgSF members, ALCAM is broadly expressed and involved in cellular adhesion across many cellular processes. While the redundancy of intercellular adhesion molecules (CAMs) could diminish the impact of any single CAM, consistent correlation between ALCAM expression and patient outcome for multiple cancers underscores its role in tumor progression. Unlike most oncogenes and tumor suppressors, ALCAM is neither mutated nor amplified or deleted. Experimental disruption of ALCAM-mediated adhesions implies that this IgSF member contributes to tumor progression through dynamic turnover of the protein at the cell surface. Since ALCAM is not frequently altered at the gene level, it appears to promote malignant behavior through regulation of its availability rather than its specific activity. These observations help explain its heterogeneous expression within malignant disease and the drastic changes in protein levels across tumor progression. To reveal how ALCAM contributes to tumor progression, we review regulation of its gene expression, alternative splicing, targeted proteolysis, binding partners, and surface shedding within the context of cancer. Studying ALCAM regulation has led to a novel understanding of the fine-tuning of cell adhesive state through the utilization of otherwise normal regulatory processes, which thereby enable tumor cell invasion and metastasis.
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8 MeSH Terms
Serine Threonine Kinase 17A Maintains the Epithelial State in Colorectal Cancer Cells.
Short SP, Thompson JJ, Bilotta AJ, Chen X, Revetta FL, Washington MK, Williams CS
(2019) Mol Cancer Res 17: 882-894
MeSH Terms: Apoptosis Regulatory Proteins, Cell Line, Tumor, Cell Movement, Colorectal Neoplasms, Epithelial Cells, Epithelial-Mesenchymal Transition, Fluorouracil, HCT116 Cells, Humans, Neoplasm Metastasis, Protein-Serine-Threonine Kinases
Show Abstract · Added April 15, 2019
Serine threonine kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer has not been established. Here, we have analyzed STK17A in colorectal cancer and demonstrated decreased expression of STK17A in primary tumors, which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of colorectal cancer cell lines to treatment with the chemotherapeutic 5-fluorouracil. Instead, knockdown induced a robust mesenchymal phenotype consistent with the epithelial-mesenchymal transition, including spindle-like cell morphology, decreased expression of adherens junction proteins, and increased migration and invasion. Additionally, overexpression of decreased cell size and induced widespread membrane blebbing, a phenotype often associated with activation of cell contractility. Indeed, STK17A-overexpressing cells displayed heightened phosphorylation of myosin light chain in a manner dependent on STK17A catalytic activity. Finally, patient-derived tumor organoid cultures were used to more accurately determine STK17A's effect in primary human tumor cells. Loss of STK17A induced morphologic changes, decreased E-cadherin, increased invasion, and augmented organoid attachment on 2D substrates, all together suggesting a more metastatic phenotype. Collectively, these data indicate a novel role for STK17A in the regulation of epithelial phenotypes and indicate its functional contribution to colorectal cancer invasion and metastasis. IMPLICATIONS: Loss of serine threonine kinase 17A occurs in colorectal cancer metastasis, induces mesenchymal morphologies, and contributes to tumor cell invasion and migration in colorectal cancer.
©2019 American Association for Cancer Research.
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11 MeSH Terms
Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model.
Colon S, Luan H, Liu Y, Meyer C, Gewin L, Bhave G
(2019) Am J Physiol Renal Physiol 316: F360-F371
MeSH Terms: Animals, Cell Movement, Disease Models, Animal, Eosinophil Peroxidase, Eosinophils, Extracellular Matrix Proteins, Female, Fibrosis, Kidney, Male, Mice, Inbred C57BL, Mice, Knockout, Nephritis, Interstitial, Peroxidase, Peroxidases, Reactive Oxygen Species, Signal Transduction, Ureteral Obstruction
Show Abstract · Added March 26, 2019
Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (HO). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize HO into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.
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18 MeSH Terms
Substrate stiffness heterogeneities disrupt endothelial barrier integrity in a micropillar model of heterogeneous vascular stiffening.
VanderBurgh JA, Hotchkiss H, Potharazu A, Taufalele PV, Reinhart-King CA
(2018) Integr Biol (Camb) 10: 734-746
MeSH Terms: Adherens Junctions, Animals, Aorta, Atherosclerosis, Cattle, Cell Adhesion, Cell Communication, Cell Movement, Dimethylpolysiloxanes, Endothelial Cells, Endothelium, Vascular, Focal Adhesions, Human Umbilical Vein Endothelial Cells, Humans, Leukocytes, Materials Testing, Neutrophils, Phenotype, Tunica Intima, Vascular Stiffness, Vinculin
Show Abstract · Added April 10, 2019
Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates. We found equivalent disruption of adherens junctions within monolayers on step-rigidity and uniformly stiff substrates relative to uniformly compliant substrates. Similarly, monolayers cultured on step-rigidity substrates exhibited equivalent percentages of leukocyte transmigration to monolayers on rigidity-matched, uniformly stiff substrates. Adherens junction tension and focal adhesion density, but not size, increased within monolayers on step-rigidity and uniformly stiff substrates compared to more compliant substrates suggesting that elevated tension is disrupting adherens junction integrity. Leukocyte transmigration frequency and time, focal adhesion size, and focal adhesion density did not differ between stiff and compliant sub-regions of step-rigidity substrates. Overall, our results suggest that endothelial monolayers exposed to mechanically heterogeneous substrates adopt the phenotype associated with the stiffer matrix, indicating that spatial heterogeneities in intimal stiffness observed with age could disrupt endothelial barrier integrity and contribute to atherogenesis.
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21 MeSH Terms
Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice.
Brandt SL, Wang S, Dejani NN, Klopfenstein N, Winfree S, Filgueiras L, McCarthy BP, Territo PR, Serezani CH
(2018) JCI Insight 3:
MeSH Terms: Abscess, Animals, Bacterial Load, Cell Movement, Chemokines, Cytokines, Diabetes Mellitus, Experimental, Female, Inflammation, Leukotriene B4, Macrophages, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Receptors, Leukotriene B4, Signal Transduction, Skin, Staphylococcal Skin Infections
Show Abstract · Added March 18, 2020
Poorly controlled diabetes leads to comorbidities and enhanced susceptibility to infections. While the immune components involved in wound healing in diabetes have been studied, the components involved in susceptibility to skin infections remain unclear. Here, we examined the effects of the inflammatory lipid mediator leukotriene B4 (LTB4) signaling through its receptor B leukotriene receptor 1 (BLT1) in the progression of methicillin-resistant Staphylococcus aureus (MRSA) skin infection in 2 models of diabetes. Diabetic mice produced higher levels of LTB4 in the skin, which correlated with larger nonhealing lesion areas and increased bacterial loads compared with nondiabetic mice. High LTB4 levels were also associated with dysregulated cytokine and chemokine production, excessive neutrophil migration but impaired abscess formation, and uncontrolled collagen deposition. Both genetic deletion and topical pharmacological BLT1 antagonism restored inflammatory response and abscess formation, followed by a reduction in the bacterial load and lesion area in the diabetic mice. Macrophage depletion in diabetic mice limited LTB4 production and improved abscess architecture and skin host defense. These data demonstrate that exaggerated LTB4/BLT1 responses mediate a derailed inflammatory milieu that underlies poor host defense in diabetes. Prevention of LTB4 production/actions could provide a new therapeutic strategy to restore host defense in diabetes.
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MeSH Terms
Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential.
Reis-Sobreiro M, Chen JF, Novitskaya T, You S, Morley S, Steadman K, Gill NK, Eskaros A, Rotinen M, Chu CY, Chung LWK, Tanaka H, Yang W, Knudsen BS, Tseng HR, Rowat AC, Posadas EM, Zijlstra A, Di Vizio D, Freeman MR
(2018) Cancer Res 78: 6086-6097
MeSH Terms: Animals, Apoptosis, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, Cell Nucleus, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Male, Membrane Proteins, Mice, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplastic Cells, Circulating, Nuclear Envelope, Nuclear Proteins, Prostatic Neoplasms
Show Abstract · Added April 10, 2019
Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator, Diaphanous-related formin 3 (DIAPH3), or the nuclear membrane-associated proteins, lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein, emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues, and in circulating tumor cells from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis. This study identifies a novel mechanism integrating the control of nuclear structure with the metastatic phenotype, and our inclusion of two types of human specimens (cancer tissues and circulating tumor cells) demonstrates direct relevance to human cancer. http://cancerres.aacrjournals.org/content/canres/78/21/6086/F1.large.jpg .
©2018 American Association for Cancer Research.
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19 MeSH Terms