Publications by authors named "Konstantinos Konstantopoulos"

151 Publications

Intrinsic epigenetic control of angiogenesis in induced pluripotent stem cell-derived endothelium regulates vascular regeneration.

NPJ Regen Med 2022 May 12;7(1):28. Epub 2022 May 12.

Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology, Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD, 21218, USA.

Human-induced pluripotent stem cell-derived endothelial cells (iECs) provide opportunities to study vascular development and regeneration, develop cardiovascular therapeutics, and engineer model systems for drug screening. The differentiation and characterization of iECs are well established; however, the mechanisms governing their angiogenic phenotype remain unknown. Here, we aimed to determine the angiogenic phenotype of iECs and the regulatory mechanism controlling their regenerative capacity. In a comparative study with HUVECs, we show that iECs increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) mediates their highly angiogenic phenotype via regulation of glycolysis enzymes, filopodia formation, VEGF mediated migration, and robust sprouting. We find that the elevated expression of VEGFR2 is epigenetically regulated via intrinsic acetylation of histone 3 at lysine 27 by histone acetyltransferase P300. Utilizing a zebrafish xenograft model, we demonstrate that the ability of iECs to promote the regeneration of the amputated fin can be modulated by P300 activity. These findings demonstrate how the innate epigenetic status of iECs regulates their phenotype with implications for their therapeutic potential.
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http://dx.doi.org/10.1038/s41536-022-00223-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098630PMC
May 2022

Kidney epithelial cells are active mechano-biological fluid pumps.

Nat Commun 2022 Apr 28;13(1):2317. Epub 2022 Apr 28.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States.

The role of mechanical forces driving kidney epithelial fluid transport and morphogenesis in kidney diseases is unclear. Here, using a microfluidic platform to recapitulate fluid transport activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, in a manner similar to mechanical fluid pumps. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human Autosomal Dominant Polycystic Kidney Disease cells, the fluidic flux is reversed from basal to apical. Molecular and proteomic studies reveal that renal epithelial cells are sensitive to hydraulic pressure gradients, changing gene expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results implicate mechanical force and hydraulic pressure as important variables during kidney function and morphological change, and provide insights into pathophysiological mechanisms underlying the development and transduction of hydraulic pressure gradients.
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http://dx.doi.org/10.1038/s41467-022-29988-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050750PMC
April 2022

Hyaluronan receptor CD44: developmentally regulated expression and role in the early chick embryo.

Int J Dev Biol 2022 Feb 21. Epub 2022 Feb 21.

Division of Genetics and Cell and Developmental Biology, Department ofBiology, University of Patras, Patras, Greece.

CD44 is a membrane glycoprotein and is the main receptor for hyaluronan. We studied the CD44 expression and spatio-temporal distribution by RT-PCR and immunofluorescence, and used an anti-CD44 blocking antibody to perturb CD44-depended signalling programs in the early chick embryo. The intense CD44 levels we detected in the morula embryo (XI) were of novel interest suggestive of a maternally stored transcript. Intriguingly, the CD44 early presence seemed to be essential for the rapid synthesis of hyaluronan. At stage XIII (blastula), CD44 expression was intense in the epiblast and hypoblast. During gastrulation (HH3-4), the cells ingressing into the primitive groove and migrating and the blood islands expressed CD44 intensely. At HH8, the folding neural plate showed polarity regulation of CD44 expression, and expression was also intense in neural crest, notochord, and blood islands. During early organogenesis, CD44 was expressed intensely in the developing cranial and caudal neural tube which showed polarity regulation, in optic stalks, otic vesicles, pre-and migratory neural crest cells, ganglia, notochord, pharynx, gut, liver, aortae, heart, somites, vascular area, amnion, chorion and was distinct in extracellular matrix of cranial neural tube and otic vesicle lumens. Antibody-mediated perturbation of CD44 function resulted in unorganized extracellular matrix, loss of tissue spaces, grossly abnormal notochord, intermingling of clumped neuroectoderm and mesenchyme, absence of somites and blood vessels, inhibition of neural crest cell emigration. CD44 has various pivotal roles in matrix integrity and tissue patterning consistent with its known biochemical features and interactions with hyaluronan, growth factors, receptors and other signaling molecules.
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http://dx.doi.org/10.1387/ijdb.220008nzDOI Listing
February 2022

Giant obscurin regulates migration and metastasis via RhoA-dependent cytoskeletal remodeling in pancreatic cancer.

Cancer Lett 2022 02 23;526:155-167. Epub 2021 Nov 23.

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA. Electronic address:

Obscurins, encoded by the OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. Large scale omics analyses reveal that OBSCN is highly mutated across different types of cancer, exhibiting a 5-8% mutation frequency in pancreatic cancer. Yet, the functional role of OBSCN in pancreatic cancer progression and metastasis has to be delineated. We herein show that giant obscurins are highly expressed in normal pancreatic tissues, but their levels are markedly reduced in pancreatic ductal adenocarcinomas. Silencing of giant obscurins in non-tumorigenic Human Pancreatic Ductal Epithelial (HPDE) cells and obscurin-expressing Panc5.04 pancreatic cancer cells induces an elongated, spindle-like morphology and faster cell migration via cytoskeletal remodeling. Specifically, depletion of giant obscurins downregulates RhoA activity, which in turn results in reduced focal adhesion density, increased microtubule growth rate and faster actin dynamics. Although OBSCN knockdown is not sufficient to induce de novo tumorigenesis, it potentiates tumor growth in a subcutaneous implantation model and exacerbates metastasis in a hemispleen murine model of pancreatic cancer metastasis, thereby shortening survival. Collectively, these findings reveal a critical role of giant obscurins as tumor suppressors in normal pancreatic epithelium whose loss of function induces RhoA-dependent cytoskeletal remodeling, and promotes cell migration, tumor growth and metastasis.
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http://dx.doi.org/10.1016/j.canlet.2021.11.016DOI Listing
February 2022

Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor.

JCI Insight 2021 10 8;6(19). Epub 2021 Oct 8.

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.
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http://dx.doi.org/10.1172/jci.insight.147612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525646PMC
October 2021

The fluid shear stress sensor TRPM7 regulates tumor cell intravasation.

Sci Adv 2021 Jul 9;7(28). Epub 2021 Jul 9.

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.

Tumor cell intravasation preferentially occurs in regions of low fluid shear because high shear is detrimental to tumor cells. Here, we describe a molecular mechanism by which cells avoid high shear during intravasation. The transition from migration to intravasation was modeled using a microfluidic device where cells migrating inside longitudinal tissue-like microchannels encounter an orthogonal channel in which fluid flow induces physiological shear stresses. This approach was complemented with intravital microscopy, patch-clamp, and signal transduction imaging techniques. Fluid shear-induced activation of the transient receptor potential melastatin 7 (TRPM7) channel promotes extracellular calcium influx, which then activates RhoA/myosin-II and calmodulin/IQGAP1/Cdc42 pathways to coordinate reversal of migration direction, thereby avoiding shear stress. Cells displaying higher shear sensitivity due to higher TRPM7 activity levels intravasate less efficiently and establish less invasive metastatic lesions. This study provides a mechanistic interpretation for the role of shear stress and its sensor, TRPM7, in tumor cell intravasation.
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http://dx.doi.org/10.1126/sciadv.abh3457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270498PMC
July 2021

Hydraulic resistance induces cell phenotypic transition in confinement.

Sci Adv 2021 04 23;7(17). Epub 2021 Apr 23.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

Cells penetrating into confinement undergo mesenchymal-to-amoeboid transition. The topographical features of the microenvironment expose cells to different hydraulic resistance levels. How cells respond to hydraulic resistance is unknown. We show that the cell phenotype shifts from amoeboid to mesenchymal upon increasing resistance. By combining automated morphological tracking and wavelet analysis along with fluorescence recovery after photobleaching (FRAP), we found an oscillatory phenotypic transition that cycles from blebbing to short, medium, and long actin network formation, and back to blebbing. Elevated hydraulic resistance promotes focal adhesion maturation and long actin filaments, thereby reducing the period required for amoeboid-to-mesenchymal transition. The period becomes independent of resistance upon blocking the mechanosensor TRPM7. Mathematical modeling links intracellular calcium oscillations with actomyosin turnover and force generation and recapitulates experimental data. We identify hydraulic resistance as a critical physical cue controlling cell phenotype and present an approach for connecting fluorescent signal fluctuations to morphological oscillations.
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http://dx.doi.org/10.1126/sciadv.abg4934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064631PMC
April 2021

A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin Axes.

Cancer Discov 2021 05 6;11(5):1138-1157. Epub 2021 Jan 6.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The existence of distinct breast microbiota has been recently established, but their biological impact in breast cancer remains elusive. Focusing on the shift in microbial community composition in diseased breast compared with normal breast, we identified the presence of in cancerous breast. Mammary gland as well as gut colonization with enterotoxigenic (ETBF), which secretes toxin (BFT), rapidly induces epithelial hyperplasia in the mammary gland. Breast cancer cells exposed to BFT exhibit "BFT memory" from the initial exposure. Intriguingly, gut or breast duct colonization with ETBF strongly induces growth and metastatic progression of tumor cells implanted in mammary ducts, in contrast to nontoxigenic . This work sheds light on the oncogenic impact of a procarcinogenic colon bacterium ETBF on breast cancer progression, implicates the β-catenin and Notch1 axis as its functional mediators, and proposes the concept of "BFT memory" that can have far-reaching biological implications after initial exposure to ETBF. SIGNIFICANCE: is an inhabitant of breast tissue, and gut or mammary duct colonization with ETBF triggers epithelial hyperplasia and augments breast cancer growth and metastasis. Short-term exposure to BFT elicits a "BFT memory" with long-term implications, functionally mediated by the β-catenin and Notch1 pathways..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0537DOI Listing
May 2021

Myosin 10 Regulates Invasion, Mitosis, and Metabolic Signaling in Glioblastoma.

iScience 2020 Dec 13;23(12):101802. Epub 2020 Nov 13.

Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Invasion and proliferation are defining phenotypes of cancer, and in glioblastoma blocking one stimulates the other, implying that effective therapy must inhibit both, ideally through a single target that is also dispensable for normal tissue function. The molecular motor myosin 10 meets these criteria. Myosin 10 knockout mice can survive to adulthood, implying that normal cells can compensate for its loss; its deletion impairs invasion, slows proliferation, and prolongs survival in murine models of glioblastoma. Myosin 10 deletion also enhances tumor dependency on the DNA damage and the metabolic stress responses and induces synthetic lethality when combined with inhibitors of these processes. Our results thus demonstrate that targeting myosin 10 is active against glioblastoma by itself, synergizes with other clinically available therapeutics, may have acceptable side effects in normal tissues, and has potential as a heretofore unexplored therapeutic approach for this disease.
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http://dx.doi.org/10.1016/j.isci.2020.101802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702012PMC
December 2020

The importance of water and hydraulic pressure in cell dynamics.

J Cell Sci 2020 10 21;133(20). Epub 2020 Oct 21.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA

All mammalian cells live in the aqueous medium, yet for many cell biologists, water is a passive arena in which proteins are the leading players that carry out essential biological functions. Recent studies, as well as decades of previous work, have accumulated evidence to show that this is not the complete picture. Active fluxes of water and solutes of water can play essential roles during cell shape changes, cell motility and tissue function, and can generate significant mechanical forces. Moreover, the extracellular resistance to water flow, known as the hydraulic resistance, and external hydraulic pressures are important mechanical modulators of cell polarization and motility. For the cell to maintain a consistent chemical environment in the cytoplasm, there must exist an intricate molecular system that actively controls the cell water content as well as the cytoplasmic ionic content. This system is difficult to study and poorly understood, but ramifications of which may impact all aspects of cell biology from growth to metabolism to development. In this Review, we describe how mammalian cells maintain the cytoplasmic water content and how water flows across the cell surface to drive cell movement. The roles of mechanical forces and hydraulic pressure during water movement are explored.
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http://dx.doi.org/10.1242/jcs.240341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595697PMC
October 2020

A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma.

Nat Biomed Eng 2021 01 28;5(1):26-40. Epub 2020 Sep 28.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.

Clinical scores, molecular markers and cellular phenotypes have been used to predict the clinical outcomes of patients with glioblastoma. However, their clinical use has been hampered by confounders such as patient co-morbidities, by the tumoral heterogeneity of molecular and cellular markers, and by the complexity and cost of high-throughput single-cell analysis. Here, we show that a microfluidic assay for the quantification of cell migration and proliferation can categorize patients with glioblastoma according to progression-free survival. We quantified with a composite score the ability of primary glioblastoma cells to proliferate (via the protein biomarker Ki-67) and to squeeze through microfluidic channels, mimicking aspects of the tight perivascular conduits and white-matter tracts in brain parenchyma. The assay retrospectively categorized 28 patients according to progression-free survival (short-term or long-term) with an accuracy of 86%, predicted time to recurrence and correctly categorized five additional patients on the basis of survival prospectively. RNA sequencing of the highly motile cells revealed differentially expressed genes that correlated with poor prognosis. Our findings suggest that cell-migration and proliferation levels can predict patient-specific clinical outcomes.
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http://dx.doi.org/10.1038/s41551-020-00621-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855796PMC
January 2021

Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion.

Int J Mol Sci 2020 Aug 28;21(17). Epub 2020 Aug 28.

Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, Spain.

Aberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This study addresses the effect of α2,3-STs knockdown on the migratory and invasive phenotype of PDA cells, and on E-selectin-dependent adhesion. Characterization of the cell sialome, the α2,3-STs and fucosyltransferases involved in the biosynthesis of sLe antigens, using a panel of human PDA cells showed differences in the levels of sialylated determinants and α2,3-STs expression, reflecting their phenotypic heterogeneity. Knockdown of ST3GAL3 and ST3GAL4 in BxPC-3 and Capan-1 cells, which expressed moderate to high levels of sLe antigens and α2,3-STs, led to a significant reduction in sLe and in most cases in sLe, with slight increases in the α2,6-sialic acid content. Moreover, ST3GAL3 and ST3GAL4 downregulation resulted in a significant decrease in cell migration and invasion. Binding and rolling to E-selectin, which represent key steps in metastasis, were also markedly impaired in the α2,3-STs knockdown cells. Our results indicate that inhibition of ST3GAL3 and ST3GAL4 may be a novel strategy to block PDA metastasis, which is one of the reasons for its dismal prognosis.
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http://dx.doi.org/10.3390/ijms21176239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503936PMC
August 2020

Dorsoventral polarity directs cell responses to migration track geometries.

Sci Adv 2020 07 31;6(31):eaba6505. Epub 2020 Jul 31.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

How migrating cells differentially adapt and respond to extracellular track geometries remains unknown. Using intravital imaging, we demonstrate that invading cells exhibit dorsoventral (top-to-bottom) polarity in vivo. To investigate the impact of dorsoventral polarity on cell locomotion through different confining geometries, we fabricated microchannels of fixed cross-sectional area, albeit with distinct aspect ratios. Vertical confinement, exerted along the dorsoventral polarity axis, induces myosin II-dependent nuclear stiffening, which results in RhoA hyperactivation at the cell poles and slow bleb-based migration. In lateral confinement, directed perpendicularly to the dorsoventral polarity axis, the absence of perinuclear myosin II fails to increase nuclear stiffness. Hence, cells maintain basal RhoA activity and display faster mesenchymal migration. In summary, by integrating microfabrication, imaging techniques, and intravital microscopy, we demonstrate that dorsoventral polarity, observed in vivo and in vitro, directs cell responses in confinement by spatially tuning RhoA activity, which controls bleb-based versus mesenchymal migration.
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http://dx.doi.org/10.1126/sciadv.aba6505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399493PMC
July 2020

Cancer cells display increased migration and deformability in pace with metastatic progression.

FASEB J 2020 07 28;34(7):9307-9315. Epub 2020 May 28.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.

In this study, we explored the relation between metastatic states vs the capacity of confined migration, amoeboid transition, and cellular stiffness. We compared across an isogenic panel of human breast cancer cells derived from MDA-MB-231 cells. It was observed that cells after lung metastasis have the fastest migration and lowest stiffness, with a significantly higher capacity to transition into an amoeboid mode. Our findings illustrate that metastasis is a selective process favoring motile and softer cells. Moreover, the observation that circulating tumor cells resemble the parental cell line, but not lung-metastatic cells, suggests that cells with higher deformability and motility are likely selected during extravasation and colonization.
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http://dx.doi.org/10.1096/fj.202000101RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547847PMC
July 2020

Exploitation of Drosophila Choriogenesis Process as a Model Cellular System for Assessment of Compound Toxicity: the Phloroglucinol Paradigm.

Sci Rep 2020 01 14;10(1):242. Epub 2020 Jan 14.

Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.

Phloroglucinol (1,3,5 tri-hydroxy-benzene) (PGL), a natural phenolic substance, is a peroxidase inhibitor and has anti-oxidant, anti-diabetic, anti-inflammatory, anti-thrombotic, radio-protective, spasmolytic and anti-cancer activities. PGL, as a medicine, is administered to patients to control the symptoms of irritable bowel syndrome and acute renal colic, in clinical trials. PGL, as a phenolic substance, can cause cytotoxic effects. Administration of PGL up to 300 mg/kg (bw) is well tolerated by animals, while in cell lines its toxicity is developed at concentrations above the dose of 10 μg/ml. Furthermore, it seems that tumor or immortalized cells are more susceptible to the toxic power of PGL, than normal cells. However, studies of its cytotoxic potency, at the cellular level, in complex, differentiated and meta-mitotic biological systems, are still missing. In the present work, we have investigated the toxic activity of PGL in somatic epithelial cells, constituting the follicular compartment of a developing egg-chamber (or, follicle), which directs the choriogenesis (i.e. chorion assembly) process, during late oogenesis of Drosophila melanogaster. Our results reveal that treatment of in vitro growing Drosophila follicles with PGL, at a concentration of 0.2 mM (or, 25.2 μg/ml), does not lead to follicle-cell toxicity, since the protein-synthesis program and developmental pattern of choriogenesis are normally completed. Likewise, the 1 mM dose of PGL was also characterized by lack of toxicity, since the chorionic proteins were physiologically synthesized and the chorion structure appeared unaffected, except for a short developmental delay, being observed. In contrast, concentrations of 10, 20 or 40 mM of PGL unveiled a dose-dependent, increasing, toxic effect, being initiated by interruption of protein synthesis and disassembly of cell-secretory machinery, and, next, followed by fragmentation of the granular endoplasmic reticulum (ER) into vesicles, and formation of autophagic vacuoles. Follicle cells enter into an apoptotic process, with autophagosomes and large vacuoles being formed in the cytoplasm, and nucleus showing protrusions, granular nucleolus and condensed chromatin. PGL, also, proved able to induce disruption of nuclear envelope, activation of nucleus autophagy (nucleophagy) and formation of a syncytium-like pattern being produced by fusion of plasma membranes of two or more individual follicle cells. Altogether, follicle cell-dependent choriogenesis in Drosophila has been herein presented as an excellent, powerful and reliable multi-cellular, differentiated, model biological (animal) system for drug-cytotoxicity assessment, with the versatile compound PGL serving as a characteristic paradigm. In conclusion, PGL is a substance that may act beneficially for a variety of pathological conditions and can be safely used for differentiated somatic -epithelial- cells at clinically low concentrations. At relatively high doses, it could potentially induce apoptotic and autophagic cell death, thus being likely exploited as a therapeutic agent against a number of pathologies, including human malignancies.
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http://dx.doi.org/10.1038/s41598-019-57113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959335PMC
January 2020

TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties.

Breast Cancer Res Treat 2020 Feb 10;179(3):631-642. Epub 2019 Dec 10.

The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background/purpose: TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition.

Experimental Design/methods: To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression.

Results: TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells.

Conclusions: Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.
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http://dx.doi.org/10.1007/s10549-019-05506-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337566PMC
February 2020

Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing.

J Cell Biol 2019 12 5;218(12):4093-4111. Epub 2019 Nov 5.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD

Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.
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http://dx.doi.org/10.1083/jcb.201902057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891075PMC
December 2019

Cell sensing and decision-making in confinement: The role of TRPM7 in a tug of war between hydraulic pressure and cross-sectional area.

Sci Adv 2019 07 24;5(7):eaaw7243. Epub 2019 Jul 24.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

How cells sense hydraulic pressure and make directional choices in confinement remains elusive. Using trifurcating Ψ-like microchannels of different hydraulic resistances and cross-sectional areas, we discovered that the TRPM7 ion channel is the critical mechanosensor, which directs decision-making of blebbing cells toward channels of lower hydraulic resistance irrespective of their cross-sectional areas. Hydraulic pressure-mediated TRPM7 activation triggers calcium influx and supports a thicker cortical actin meshwork containing an elevated density of myosin-IIA. Cortical actomyosin shields cells against external forces and preferentially directs cell entrance in low resistance channels. Inhibition of TRPM7 function or actomyosin contractility renders cells unable to sense different resistances and alters the decision-making pattern to cross-sectional area-based partition. Cell distribution in microchannels is captured by a mathematical model based on the maximum entropy principle using cortical actin as a key variable. This study demonstrates the unique role of TRPM7 in controlling decision-making and navigating migration in complex microenvironments.
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http://dx.doi.org/10.1126/sciadv.aaw7243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656542PMC
July 2019

A Unique Case of Primary Extranodal Marginal Zone Lymphoma of the Anal Canal.

Acta Haematol 2019 17;142(2):87-91. Epub 2019 Jun 17.

Department of Hematology, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece,

Marginal zone lymphomas represent approximately 10-12% of all B-cell lymphomas. Extranodal marginal zone lymphomas (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphomas are the most common subtype. Almost half of all MALT lymphomas arise in the gastrointestinal (GI) tract and, while the stomach is the most common site of GI involvement, the small and large intestines can also be involved. Rare cases of MALT lymphoma involving the rectum have been reported; however, to our knowledge, involvement of the anal canal has never been reported in the literature. Here, we describe a unique case of MALT lymphoma of the anal canal. Infectious agents have been implicated in the pathogenesis of MALT lymphomas, possibly through persistent antigenic stimulation of the area; however, in our case no such infection was documented.
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http://dx.doi.org/10.1159/000495601DOI Listing
February 2020

A microfluidic assay for the quantification of the metastatic propensity of breast cancer specimens.

Nat Biomed Eng 2019 06 6;3(6):452-465. Epub 2019 May 6.

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.

The challenge of predicting which patients with breast cancer will develop metastases leads to the overtreatment of patients with benign disease and to the inadequate treatment of aggressive cancers. Here, we report the development and testing of a microfluidic assay that quantifies the abundance and proliferative index of migratory cells in breast cancer specimens, for the assessment of their metastatic propensity and for the rapid screening of potential antimetastatic therapeutics. On the basis of the key roles of cell motility and proliferation in cancer metastasis, the device accurately predicts the metastatic potential of breast cancer cell lines and of patient-derived xenografts. Compared with unsorted cancer cells, highly motile cells isolated by the device exhibited similar tumourigenic potential but markedly increased metastatic propensity in vivo. RNA sequencing of the highly motile cells revealed an enrichment of motility-related and survival-related genes. The approach might be developed into a companion assay for the prediction of metastasis in patients and for the selection of effective therapeutic regimens.
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http://dx.doi.org/10.1038/s41551-019-0400-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563615PMC
June 2019

A Direct Podocalyxin-Dynamin-2 Interaction Regulates Cytoskeletal Dynamics to Promote Migration and Metastasis in Pancreatic Cancer Cells.

Cancer Res 2019 06 11;79(11):2878-2891. Epub 2019 Apr 11.

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.

The sialoglycoprotein podocalyxin is absent in normal pancreas but is overexpressed in pancreatic cancer and is associated with poor clinical outcome. Here, we investigate the role of podocalyxin in migration and metastasis of pancreatic adenocarcinomas using SW1990 and Pa03c as cell models. Although ezrin is regarded as a cytoplasmic binding partner of podocalyxin that regulates actin polymerization via Rac1 or RhoA, we did not detect podocalyxin-ezrin association in pancreatic cancer cells. Moreover, depletion of podocalyxin did not alter actin dynamics or modulate Rac1 and RhoA activities in pancreatic cancer cells. Using mass spectrometry, bioinformatics analysis, coimmunoprecipitation, and pull-down assays, we discovered a novel, direct binding interaction between the cytoplasmic tail of podocalyxin and the large GTPase dynamin-2 at its GTPase, middle, and pleckstrin homology domains. This podocalyxin-dynamin-2 interaction regulated microtubule growth rate, which in turn modulated focal adhesion dynamics and ultimately promoted efficient pancreatic cancer cell migration via microtubule- and Src-dependent pathways. Depletion of podocalyxin in a hemispleen mouse model of pancreatic cancer diminished liver metastasis without altering primary tumor size. Collectively, these findings reveal a novel mechanism by which podocalyxin facilitates pancreatic cancer cell migration and metastasis. SIGNIFICANCE: These findings reveal that a novel interaction between podocalyxin and dynamin-2 promotes migration and metastasis of pancreatic cancer cells by regulating microtubule and focal adhesion dynamics.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548656PMC
June 2019

Diagnostic role of cytology in serous effusions of patients with hematologic malignancies.

Diagn Cytopathol 2019 May 12;47(5):404-411. Epub 2018 Nov 12.

Department of Cytopathology, Laiko Hospital of Athens, Athens, Greece.

Background: We investigated serous effusions occurring during the course of an already known hematologic neoplasia or as a first manifestation of it. We correlated cytology results with flow cytometry results, when available. In the absence of flow cytometry, our correlation was based on clinical follow up information obtained retrospectively. We evaluated our results in relation to the data of the literature and we considered some new suggestions for the improvement of cytology service.

Methods: Serous effusions in hematologic patients were retrieved from the files of the Department of Cytology, Laiko Hospital, for a period of 2 years. All patients had enrolled either a previous hematologic history, or a suspicious clinical and imaging status. Seventy-three serous effusions were included. Cytology reports consisting of morphology and immunocytochemistry assessment were correlated to flow cytometry results and, occasionally, to clinical follow-up.

Results: In the group of patients with previous history, sensitivity was 82.76%, positive predictive value was 100%, specificity 100%, and negative predictive value was 58.33%. In the group of patients without previous history, sensitivity and positive predictive value were both 91%, whereas specificity and negative predictive value could not be estimated.

Conclusion: We provide evidence that the diagnostic accuracy of cytology with the adjunct of immunocytochemistry is high compared to flow cytometry for detecting hematologic malignancies. In order to improve clinical performance, it is suggested that a cytology triage of serous effusions in all patients with hematologic malignancy must be implemented.
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http://dx.doi.org/10.1002/dc.24110DOI Listing
May 2019

Exposing Cell-Itary Confinement: Understanding the Mechanisms of Confined Single Cell Migration.

Adv Exp Med Biol 2018;1092:139-157

Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.

Cells in vivo migrate in a complex microenvironment and are subjected to varying degrees of physical confinement provided by neighboring cells, tissues, and extracellular matrix. The molecular machinery that cells utilize to migrate through confining pores or microtracks shares both similarities and differences with that used in unconfined 2D migration. Depending on the exact properties of the local microenvironment and cell contractile state, cells can adopt distinct phenotypes and employ a wide array of mechanisms to migrate efficiently in confined spaces. Remarkably, these various migration modes are also interconvertible and interconnected, highlighting the plasticity and inherent complexity underlying confined cell migration. In this book chapter, an overview of the different molecular mechanisms utilized by cells to migrate in confinement is presented, with special emphasis on the extrinsic environmental and intrinsic molecular determinants that control the transformation from one mechanism to the other.
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http://dx.doi.org/10.1007/978-3-319-95294-9_8DOI Listing
July 2019

16s rRNA gene sequencing and radioisotopic analysis reveal the composition of ammonia acclimatized methanogenic consortia.

Bioresour Technol 2019 Jan 26;272:54-62. Epub 2018 Sep 26.

Department of Environmental Engineering, Technical University of Denmark, Bygningstorvet Bygning 115, DK-2800 Kgs. Lyngby, Denmark.

Different mesophilic and thermophilic methanogenic consortia were acclimatised and enriched to extreme total ammonia (9.0 and 5.0 g NH-N L, respectively) and free ammonia (1.0 and 1.4 g NH-N L, respectively) levels in this study. [2-C] acetate radioisotopic analyses showed the dominance of aceticlastic methanogenesis in all enriched consortia. According to 16S rRNA gene sequencing result, in mesophilic consortia, methylotrophic Methanomassiliicoccus luminyensis was predominant, followed by aceticlastic Methanosarcina soligelidi. A possible scenario explaining the dominance of M. luminyensis includes the use of methylamine produced by Tissierella spp. and biomass build-up by metabolizing acetate. Nevertheless, further studies are needed to pinpoint the exact metabolic pathway of M. luminyensis. In thermophilic consortia, aceticlastic Methanosarcina thermophila was the sole dominant methanogen. Overall, results derived from this study demonstrated the efficient biomethanation ability of these ammonia-tolerant methanogenic consortia, indicating a potential application of these consortia to solve ammonia toxicity problems in future full-scale reactors.
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http://dx.doi.org/10.1016/j.biortech.2018.09.128DOI Listing
January 2019

Physical characterization of the aerosol of an electronic cigarette: impact of refill liquids.

Inhal Toxicol 2018 05 26;30(6):218-223. Epub 2018 Sep 26.

b Department of Critical Care and Pulmonary Services, "Evangelismos" Hospital, Athens Medical School , University of Athens , Athens , Greece.

Electronic cigarettes are used to evaporate a mixture of solvents, nicotine and flavors. Liquid particles can be generated under these conditions due to evaporation/condensation. The objective of this work is to measure the physical characteristics of the aerosol emission of an e-cigarette using different refill liquids. The aerosol particle number and size are determined with a Scanning Mobility Particle Sizer. Seven liquids are used: propylene glycol (PG), glycerol (VG), a mixture 1:1 of PG/VG, the mixture with 2% or 5% of a commercial flavor, the mixture with 1.2% of nicotine and the mixture with 1.2% of nicotine and 2% of flavor. Particle concentrations of the aerosol emitted from the electronic cigarette are 300-3000 times higher than that of the ambient air. Propylene glycol emits several times more than glycerol. The addition of a flavor or nicotine has little effect on the emission of the total number emitted. The count median diameter of the electronic cigarette particles is 200-400 nm, depending on the liquid used. Count median diameter of emitted particles is affected by the liquid used.
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http://dx.doi.org/10.1080/08958378.2018.1500662DOI Listing
May 2018

Positive impact of brentuximab vedotin on overall survival of patients with classical Hodgkin lymphoma who relapse or progress after autologous stem cell transplantation: A nationwide analysis.

Hematol Oncol 2018 Oct 8;36(4):645-650. Epub 2018 Jun 8.

Dept of Hematology and BMT, LAIKON Hospital, Athens, Greece.

The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after autologous stem cell transplantation (auto-SCT) is poor. Recently, the anti-CD30 monoclonal antibody-drug conjugate, brentuximab vedotin (BV), has shown remarkable activity in the setting of R/R cHL. In the pivotal phase II study, BV produced an overall response rate of 75% and a median progression-free survival of 6.7 months. Although these results have been reproduced by large registry studies, the impact of BV on the overall survival (OS) of patients with R/R cHL has not been addressed so far. The aim of this study was to examine the impact of BV on OS in the setting of post auto-SCT R/R cHL. Analysis was performed in a group of patients with R/R cHL after a previous auto-SCT reported in the Greek registry during the last 2 decades. By using a multivariate model and censoring patients at the time of subsequent allo-SCT or treatment with immune checkpoint inhibitors, we showed that treatment with BV in the posttransplant relapse setting has a positive impact on the outcome and results in significant improvement of OS. To our knowledge, this the first published study, addressing the impact of BV on the OS in the setting of posttransplant relapse.
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http://dx.doi.org/10.1002/hon.2521DOI Listing
October 2018

Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses.

Proc Natl Acad Sci U S A 2018 02 5;115(8):1925-1930. Epub 2018 Feb 5.

Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain;

Actin polymerization and assembly into stress fibers (SFs) is central to many cellular processes. However, how SFs form in response to the mechanical interaction of cells with their environment is not fully understood. Here we have identified Piezo2 mechanosensitive cationic channel as a transducer of environmental physical cues into mechanobiological responses. Piezo2 is needed by brain metastatic cells from breast cancer (MDA-MB-231-BrM2) to probe their physical environment as they anchor and pull on their surroundings or when confronted with confined migration through narrow pores. Piezo2-mediated Ca influx activates RhoA to control the formation and orientation of SFs and focal adhesions (FAs). A possible mechanism for the Piezo2-mediated activation of RhoA involves the recruitment of the Fyn kinase to the cell leading edge as well as calpain activation. Knockdown of Piezo2 in BrM2 cells alters SFs, FAs, and nuclear translocation of YAP; a phenotype rescued by overexpression of dominant-positive RhoA or its downstream effector, mDia1. Consequently, hallmarks of cancer invasion and metastasis related to RhoA, actin cytoskeleton, and/or force transmission, such as migration, extracellular matrix degradation, and Serpin B2 secretion, were reduced in cells lacking Piezo2.
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http://dx.doi.org/10.1073/pnas.1718177115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828612PMC
February 2018

Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes.

Sci Signal 2017 Nov 21;10(506). Epub 2017 Nov 21.

Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The adaptation of the skeleton to its mechanical environment is orchestrated by mechanosensitive osteocytes, largely by regulating the abundance of sclerostin, a secreted inhibitor of bone formation. We defined a microtubule-dependent mechanotransduction pathway that linked fluid shear stress to reactive oxygen species (ROS) and calcium (Ca) signals that led to a reduction in sclerostin abundance in cultured osteocytes. We demonstrated that microtubules stabilized by detyrosination, a reversible posttranslational modification of polymerized α-tubulin, determined the stiffness of the cytoskeleton, which set the mechanoresponsive range of cultured osteocytes to fluid shear stress. We showed that fluid shear stress through the microtubule network activated NADPH oxidase 2 (NOX2)-generated ROS that target the Ca channel TRPV4 to elicit Ca influx. Furthermore, tuning the abundance of detyrosinated tubulin affected cytoskeletal stiffness to define the mechanoresponsive range of cultured osteocytes to fluid shear stress. Finally, we demonstrated that NOX2-ROS elicited Ca signals that activated the kinase CaMKII to decrease the abundance of sclerostin protein. Together, these discoveries may identify potentially druggable targets for regulating osteocyte mechanotransduction to affect bone quality.
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http://dx.doi.org/10.1126/scisignal.aan5748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858867PMC
November 2017

Loss of giant obscurins alters breast epithelial cell mechanosensing of matrix stiffness.

Oncotarget 2017 Aug 1;8(33):54004-54020. Epub 2016 Aug 1.

Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA.

Obscurins are a family of RhoGEF-containing proteins with tumor and metastasis suppressing roles in breast epithelium. Downregulation of giant obscurins in normal breast epithelial cells leads to reduced levels of active RhoA and of its downstream effectors. Herein, we elucidate how depletion of giant obscurins affects the response of breast epithelial cells to changes in the mechanical properties of the microenvironment. We find that knockdown of obscurins increases cell morphodynamics, migration speed, and diffusivity on polyacrylamide gels of ≥ 1 kPa, presumably by decreasing focal adhesion area and density as well as cell traction forces. Depletion of obscurins also increases cell mechanosensitivity on soft (0.4-4 kPa) surfaces. Similar to downregulation of obscurins, pharmacological inhibition of Rho kinase in breast epithelial cells increases migration and morphodynamics, suggesting that suppression of Rho kinase activity following obscurin knockdown can account for alterations in morphodynamics and migration. In contrast, inhibition of myosin light chain kinase reduces morphodynamics and migration, suggesting that temporal changes in cell shape are required for efficient migration. Collectively, downregulation of giant obscurins facilitates cell migration through heterogeneous microenvironments of varying stiffness by altering cell mechanobiology.
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http://dx.doi.org/10.18632/oncotarget.10997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589558PMC
August 2017

E-selectin-mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid.

FASEB J 2017 11 1;31(11):5078-5086. Epub 2017 Aug 1.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA;

Tumor cell extravasation is a multistep process preceded by cell rolling and arrest on the vessel wall the formation of specific receptor-ligand bonds. The strength, availability, and number of receptor-ligand bonds regulate the rate by which tumor cells tether, roll, and adhere to vascular walls. Although the mechanics of selectin-mediated rolling have been extensively studied, little is known regarding how tumor cell rolling on selectins facilitates adhesion to a distinct substrate-bound protein with different kinetic properties. By using multicomponent protein patterning and a microfluidic system, we evaluated how E-selectin-dependent rolling modulates hyaluronic acid (HA) adhesion as a function of fluid shear, contact time, and the spacing between E-selectin and HA regions patterned on the substrate. We show that tumor cells rolling on E-selectin were ∼40-fold more likely to bind to HA than nonrolling cells in shear flow. Furthermore, E-selectin-dependent rolling promotes adhesion to HA by both physically slowing cells and enabling them to position proximal to the surface, thereby increasing the on rate of adhesion. A better understanding of tumor cell adhesion under physiologic shear would lead to the development of new diagnostic assays and pave the way to clinical approaches aimed ultimately to halt metastasis.-Shea, D. J., Li, Y. W., Stebe, K. J., Konstantopoulos, K. E-selectin-mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid.
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http://dx.doi.org/10.1096/fj.201700331RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636711PMC
November 2017
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