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Martina E.,Friedrich Miescher Institute for Biomedical Research | Degen M.,Friedrich Miescher Institute for Biomedical Research | Degen M.,Harvard University | Ruegg C.,University of Lausanne | And 5 more authors.
FASEB Journal | Year: 2010

The microenvironment hosting a tumor actively participates in regulating tumor cell proliferation, migration, and invasion. Among the extracellular matrix proteins enriched in the stroma of carcinomas are the tenascin family members tenascin-C and tenascin-W. Whereas tenascin-C overexpression in gliomas is known to correlate with poor prognosis, the status of tenascin-W in brain tumors has not been investigated so far. In the present study, we analyzed protein levels of tenascin-W in 38 human gliomas and found expression of tenascin-W in 80% of the tumor samples, whereas no tenascin-W could be detected in control, nontumoral brain tissues. Double immunohistochemical staining of tenascin-W and von Willebrand factor revealed that tenascin-W is localized around blood vessels, exclusively in tumor samples. In vitro, the presence of tenascin-W increased the proportion of elongated human umbilical vein endothelial cells (HUVECs) and augmented the mean speed of cell migration. Furthermore, tenascin-W triggered sprouting of HUVEC spheroids to a similar extent as the proangiogenic factor tenascin-C. In conclusion, our study identifies tenascin-W as a candidate biomarker for brain tumor angiogenesis that could be used as a molecular target for therapy irrespective of the glioma subtype. © The Author(s).

Tenbaum S.P.,Vall dHebron Institute dOncologia VHIO | Ordonez-Moran P.,Autonomous University of Madrid | Ordonez-Moran P.,Swiss Institute for Experimental Cancer Research | Puig I.,Vall dHebron Institute dOncologia VHIO | And 19 more authors.
Nature Medicine | Year: 2012

The Wnt-β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt-β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear b-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt-β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment. © 2012 Nature America, Inc. All rights reserved.

Levy C.,Harvard University | Khaled M.,Harvard University | Robinson K.C.,Harvard University | Veguilla R.A.,Harvard University | And 12 more authors.
Cell | Year: 2010

DICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression-an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17∼92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development. © 2010 Elsevier Inc.

News Article | November 21, 2016
Site: www.eurekalert.org

Type-1 diabetes occurs when immune cells attack the pancreas. EPFL scientists have now discovered what may trigger this attack, opening new directions for treatments. Type-1 diabetes is the rarest but most aggressive form of diabetes, usually affecting children and adolescents. The patient's own immune cells begin to attack the cells in the pancreas that make insulin, eventually eliminating its production in the body. The immune cells target certain proteins inside the insulin-producing cells. However, it is unclear how this actually happens. EPFL scientists have now discovered that the immune attack in type-1 diabetes may be triggered by the release of proteins from the pancreas itself, as well as the package they come in. The work, which has significant implications for therapy strategies, is published in Diabetes. Diabetes is a disease in which the body produces inadequate or no amounts of the hormone insulin, which regulates sugar levels in the blood. Insulin is produced by a group of cells in the pancreas called beta cells. In type-1 diabetes, the patient's immune cells specifically attack beta cells, thereby disrupting the production of insulin. However, we don't actually know what causes the immune cells to attack in the first place. Scientists from EPFL's Institute of Bioengineering, led by Steinunn Baekkeskov, have now discovered that pancreatic beta cells actually secrete proteins that are targeted by the immune attack. But it's not only the proteins that cause problems; the researchers found that it is also their packaging. That packaging comes in the form of small vesicles called exosomes, which are secreted by all cell types to distribute various molecules with different functions. But previous studies have shown that exosomes can also activate the immune system. Building on this, the EPFL researchers looked at exosomes from human and animal pancreatic beta cells. The results showed that rat and human pancreatic beta cells release three proteins known to be associated with type-1 diabetes, and are in fact used by clinicians to diagnose its onset in people. The researchers might have also discovered why the immune attack on the pancreas begins in the first place: When insulin-making beta cells were exposed to stress, they released high amounts of exosomes, which they also "decorated" with proteins that activate immune cells. These powerfully inflammatory proteins may be involved in induction of autoimmunity in the disease. The hope is that this will lead to new directions in developing more effective treatments that focus on developing exosome mimics that contain molecules inhibiting rather than stimulating immune cells. These synthetic molecules would be taken up by the patient's immune cells and would block them from attacking beta cells. This work was carried out at the EPFL's Institute of Bioengineering (IBI), by lead authors Chiara Cianciaruso and Edward A. Phelps, with contributions from EPFL's Proteomics Core Facility, Bio-Electron Microscopy Core Facility, Bio-Imaging Core Facility, the Swiss Institute for Experimental Cancer Research. It involves a collaboration with the European Consortium on Islet Transplantation (ECIT) Islets for Basic Research Program at the University Hospital of Geneva and at the San Raffaele Scientific Institute of Milan. It was funded by JDRF and EPFL. Chiara Cianciaruso, Edward A. Phelps, Miriella Pasquier, Romain Hamelin, Davide Demurtas, Mohamed Alibashe Ahmed, Lorenzo Piemonti, Sachiko Hirosue, Melody A. Swartz, Michele De Palma, Jeffrey A. Hubbell, Steinunn Baekkeskov. Primary human and rat beta cells release the intracellular autoantigens GAD65, IA-2 and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 21 November 2016. DOI: 10.2337/db16-0671

Gotze S.,Max Planck Institute of Molecular Physiology | Coersmeyer M.,Swiss Institute for Experimental Cancer Research | Muller O.,Kaiserslautern University of Applied Sciences | Sievers S.,Max Planck Institute of Molecular Physiology
International Journal of Oncology | Year: 2014

Histone deacetylase inhibitors (HDIs) specifically affect cancer cells by inducing cell cycle arrest, activate apoptotic pathways and re-activate epigenetically silenced tumor suppressor genes, but their pleiotropic mode of action is not fully understood. Despite the clinical effects of HDIs in the treatment of hematological malignancies, their potency against solid tumors is still unclear. We investigated the effects and mechanisms of HDI action in colorectal carcinoma cell lines with an activated Wnt signaling pathway, which is implicated in different aspects of tumorigenesis, including cell proliferation, apoptosis, angiogenesis and metastasis. We assessed the effects of HDI treatment in colorectal carcinoma cell lines by measuring histone hyperacetylation, cell viability and expression of Wnt target genes. Upon treatment with HDIs of the hydroxamate class, we found attenuation of Wnt signaling with concomitant induction of apoptosis and colorectal cancer cell death. Strikingly, the effects of HDIs on Wnt signaling were independent of histone hyperacetylation, thus we investigated the role of non-histone target proteins of histone deacetylases (HDACs). The compounds TSA and SAHA induced a rapid proteasome-dependent depletion of the Wnt transcription factor TCF7L2, which may be mediated by inhibition of HDAC 6 and 10. Our findings provide a molecular rationale for the use of HDIs against colorectal carcinomas with activated Wnt signaling.

News Article | November 16, 2016
Site: www.eurekalert.org

EPFL scientists have developed a gel for growing miniaturized body organs that can be used in clinical diagnostics and drug development. Organoids are miniature organs that can be grown in the lab from a person's stem cells. They can be used to model diseases, and in the future could be used to test drugs or even replace damaged tissue in patients. But currently organoids are very difficult to grow in a standardized and controlled way, which is key to designing and using them. EPFL scientists have now solved the problem by developing a patent-pending "hydrogel" that provides a fully controllable and tunable way to grow organoids. The breakthrough is published in Nature. Growing organoids begins with stem cells -- immature cells that can grow into any cell type of the human body and that play key roles in tissue function and regeneration. To form an organoid, the stem cells are grown inside three-dimensional gels that contain a mix of biomolecules that promote stem cell renewal and differentiation. The role of these gels is to mimic the natural environment of the stem cells, which provides them with a protein- and sugar-rich scaffold called the "extracellular matrix", upon which the stem cells build specific body tissues. The stem cells stick to the extracellular matrix gel, and then "self-organize" into miniature organs like retinas, kidneys, or the gut. These tiny organs retain key aspects of their real-life biology, and can be used to study diseases or test drugs before moving on to human trials. But the current gels used for organoid growth are derived from mice, and have problems. First, it is impossible to control their makeup from batch to batch, which can cause stem cells to behave inconsistently. Second, their biochemical complexity makes them very difficult to fine-tune for studying the effect of different parameters (e.g. biological molecules, mechanical properties, etc.) on the growth of organoids. Finally, the gels can carry pathogens or immunogens, which means that they are not suitable for growing organoids to be used in the clinic. The lab of Matthias Lütolf at EPFL's Institute of Bioengineering has developed a synthetic "hydrogel" that eschews the limitations of conventional, naturally derived gels. The patent-pending gel is made of water and polyethylene glycol, a substance used widely today in various forms, from skin creams and toothpastes to industrial applications and, as in this case, bioengineering. Nikolce Gjorevski, the first author of the study, and his colleagues used the hydrogel to grow stem cells of the gut into a miniature intestine. The functional hydrogel was not only a goal in and of itself, but also a means to identify the factors that influence the stem cells' ability to expand and form organoids. By carefully tweaking the hydrogel's properties, they discovered that separate stages of the organoid formation process require different mechanical environments and biological components. One such factor is a protein called fibronectin, which helps the stem cells attach to the hydrogel. Lütolf's lab found that this attachment itself is immensely important for growing organoids, as it triggers a whole host of signals to the stem cell that tell it to grow and build an intestine-like structure. The researchers also discovered an essential role for the mechanical properties, i.e. the physical stiffness, of the gel in regulating intestinal stem cell behavior, shedding light on how cells are able to sense, process and respond to physical stimuli. This insight is particularly valuable - while the influence of biochemical signals on stem cells is well-understood, the effect of physical factors has been more mysterious. Because the hydrogel is man-made, it is easy to control its chemical composition and key properties, and ensure consistency from batch to batch. And because it is artificial, it does not carry any risk of infection or triggering immune responses. As such, it provides a means of moving organoids from basic research to actual pharmaceutical and clinical applications in the future. Lütolf's lab is now researching other types of stem cells in order to extend the capacities of their hydrogel into other tissues. This work included a collaboration between EPFL's Institute of Bioengineering (IBI), Swiss Institute for Experimental Cancer Research (ISREC) and Institute of Chemical Sciences and Engineering (ISIC), with the Hubrecht Institute and University Medical Center Utrecht (Netherlands). It was funded by a European Molecular Biology Organization (EMBO) Fellowship and support from EPFL.

Mahul-Mellier A.-L.,Ecole Polytechnique Federale de Lausanne | Fauvet B.,Ecole Polytechnique Federale de Lausanne | Gysbers A.,University of New South Wales | Dikiy I.,Cornell College | And 9 more authors.
Human Molecular Genetics | Year: 2014

Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and a-synuclein (a-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39a-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD. © The Author 2014. Published by Oxford University Press. All rights reserved.Published by Oxford University Press. All rights reserved.

El-Gebali S.,University of Bern | Bentz S.,University of Bern | Hediger M.A.,University of Bern | Anderle P.,University of Bern | And 2 more authors.
Molecular Aspects of Medicine | Year: 2013

During tumor progression cells acquire an altered metabolism, either as a cause or as a consequence of an increased need of energy and nutrients. All four major classes of macromolecules are affected: carbohydrates, proteins, lipids and nucleic acids. As a result of the changed needs, solute carriers (SLCs) which are the major transporters of these molecules are differently expressed. This renders them important targets in the treatment of cancer. Blocking or activating SLCs is one possible therapeutic strategy. For example, some SLCs are upregulated in tumor cells due to the increased demand for energy and nutritional needs. Thus, blocking them and turning off the delivery of fuel or nutrients could be one way to interfere with tumor progression. Specific drug delivery to cancer cells via transporters is another approach. Some SLCs are also interesting as chemosensitizing targets because blocking or activating them may result in an altered response to chemotherapy. In this review we summarize the roles of SLCs in cancer therapy and specifically their potential as direct or indirect targets, as drug carriers or as chemosensitizing targets. © 2012 Elsevier Ltd. All rights reserved.

Yang C.,Massachusetts General Hospital | Chen L.,Massachusetts General Hospital | Li C.,Massachusetts General Hospital | Lynch M.C.,Massachusetts General Hospital | And 2 more authors.
Molecular and Cellular Biology | Year: 2010

Estrogen and progesterone are the defining hormones of normal female development, and both play critical roles in breast carcinogenesis. Cyclin D1 is a breast cancer oncogene whose amplification is linked to poor prognosis in estrogen and progesterone receptor-positive breast cancers. Here we report that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone. Estrogen treatment of cyclin D1 transgenic mice increased progesterone receptor expression and induced mammary hyperplasias that were stimulated by progesterone and blocked by a progesterone antagonist. Progesterone receptor levels decreased in cyclin D1 knockout mice. Cyclin D1 regulated progesterone receptor expression through a novel estrogen- and cyclin D1-responsive enhancer in DNA encoding part of the 3′ untranslated region of the progesterone receptor gene. Small inhibitory RNAs for cyclin D1 decreased progesterone receptor expression and estrogen receptor binding to the 3′ enhancer region in human breast cancer cells. Since estrogen and progesterone regulate cyclin D1, our results suggest that cyclin D1's participation in a feed-forward loop could contribute to increased breast cancer risks associated with estrogen and progesterone combinations. Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

News Article | December 30, 2015
Site: www.biosciencetechnology.com

​EPFL scientists have found that chronic inflammation can cause regenerating cells to grow into new, aberrant types; this is called metaplasia, and is a disorder linked to prolonged inflammation. The study highlights a new concept of chronic inflammation and could lead to better treatments. Chronic inflammation turns the immune system on for prolonged periods of time. As a result, it underlies many disorders that are associated with chronic inflammation, including cancer and abnormal wound healing. EPFL scientists have now discovered an additional component: chronic inflammation can cause cells to actually change type – here, eye cells turned into skin. The study is published in Nature Cell Biology. Many tissues contain a reserve of stem cells that help them heal and self-renew after injury or inflammation. Wanting to understand what happens under chronic inflammation conditions, a team of researchers led by Freddy Radtke at EPFL’s Swiss Institute for Experimental Cancer Research (ISREC) studied stem cells in the corneas of mice. To do this, they used methods that simulate chronic inflammation, and analyzed the data with techniques that light up specific cells with fluorescent stains. The scientists found that in the cornea, the environment of stem cells changed – specifically, it became stiffer. The reason for this is both the presence of immune cells but also an increase in a substance that helps cells stick to each other and form structures and organs. The corneal stem cells, like many other cells, have sensors that measure the stiffness of surrounding tissues and allow the cells to adapt accordingly. In short, if stiffness changes, the cells react. In the cornea, the researchers found that the cell environment became so stiff that the stem cells began to turn on wrong differentiation programs: the “software” package that tells a stem cell what cell to turn into. As a result of bad programming, the stem cells proliferated and made skin instead of cornea, causing the mice to go blind. In humans, this kind of abnormal change in the nature of a tissue is called “metaplasia”, and is associated with chronic inflammation. “Our study demonstrates an important mechanism by which chronic inflammation induces abnormal stem cell behavior,” said Freddy Radtke. “This is relevant to a variety of diseases associated with chronic inflammation, including cancer, and could yield new therapeutic targets.”

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