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1.
Rev Med Suisse ; 16(704): 1574-1578, 2020 Sep 02.
Article in French | MEDLINE | ID: mdl-32880115

ABSTRACT

Precision medicine aims to tailor prevention and treatment to individual data. Although different markers can be used (e.g. transcriptome or proteome), its rise is closely linked to that of genomics, owing to the henceforth reasonable cost of DNA sequencing. The enormous datasets thus generated can be exploited due to remarkable advances in bioinformatics and information sciences. However, beyond the technological endeavor, humanities and social sciences also play a central role to redefine health and illness. The precision medicine unit at CHUV gathers stakeholders from these various domains in order to demonstrate the utility of precision medicine and catalyze its integration into healthcare, to the benefit of the patient.


La médecine de précision a pour but d'ajuster la prévention et les traitements aux données individuelles. La génomique en est un moteur du fait du coût désormais raisonnable des analyses ADN, malgré l'utilisation possible d'autres marqueurs (transcriptome, protéome etc.). Les données massives ainsi générées peuvent être analysées grâce aux progrès de la bioinformatique et des sciences de l'information. La médecine de précision ne se résume pas à une aventure technologique : les sciences humaines et sociales y jouent un rôle central car elles promettent une redéfinition du rapport à la santé et à la maladie. L'Unité de médecine de précision du CHUV réunit les acteurs de ces différents domaines afin de démontrer l'utilité de la médecine de précision et d'accélérer son incorporation dans le parcours de soins, au bénéfice du patient.


Subject(s)
Genomics , Humanities , Medical Informatics , Molecular Biology , Precision Medicine/trends , Humans
2.
PLoS One ; 7(10): e47480, 2012.
Article in English | MEDLINE | ID: mdl-23094054

ABSTRACT

Exosomes are of increasing interest as alternative mode of cell-to-cell communication. We previously reported that exosomes secreted by human SOJ-6 pancreatic tumor cells induce (glyco)protein ligand-independent cell death and inhibit Notch-1 pathway, this latter being particularly active during carcinogenesis and in cancer stem cells. Therefore, we asked whether exosomal lipids were key-elements for cell death and hypothesized that cholesterol-rich membrane microdomains were privileged sites of exosome interactions with tumor cells. To address these questions and based on the lipid composition of exosomes from SOJ-6 cells (Ristorcelli et al. (2008) FASEB J. 22; 3358-3369) enriched in cholesterol and sphingomyelin (lipids forming liquid-ordered phase, Lo) and depleted in phospholipids (lipids forming liquid-disordered phase, Ld), we designed Synthetic Exosome-Like Nanoparticles (SELN) with ratios Lo/Ld from 3.0 to 6.0 framing that of SOJ-6 cell exosomes. SELN decreased tumor cell survival, the higher the Lo/Ld ratio, the lower the cell survival. This decreased survival was due to activation of cell death with inhibition of Notch pathway. FRET analyses indicated fusions/exchanges of SELN with cell membranes. Fluorescent SELN co-localized with the ganglioside GM1 then with Rab5A, markers of lipid microdomains and of early endosomes, respectively. These interactions occurred at lipid microdomains of plasma and/or endosome membranes where the Notch-1 pathway matures. We thus demonstrated a major role for lipids in interactions between SELN and tumor cells, and in the ensued cell death. To our knowledge this is the first report on such effects of lipidic nanoparticles on tumor cell behavior. This may have implications in tumor progression.


Subject(s)
Biomimetic Materials/pharmacology , Exosomes/metabolism , Nanoparticles/chemistry , Pancreatic Neoplasms/metabolism , Receptor, Notch1/metabolism , Biological Transport , Biomimetic Materials/chemistry , Cell Communication , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cholesterol/chemistry , Cholesterol/pharmacology , Exosomes/chemistry , G(M1) Ganglioside/chemistry , Gene Expression , Humans , Membrane Microdomains/drug effects , Microscopy, Fluorescence , Nanoparticles/ultrastructure , Pancreatic Neoplasms/ultrastructure , Receptor, Notch1/genetics , Signal Transduction , Sphingomyelins/chemistry , Sphingomyelins/pharmacology , rab5 GTP-Binding Proteins/metabolism
3.
EMBO J ; 30(22): 4571-85, 2011 Nov 16.
Article in English | MEDLINE | ID: mdl-21909072

ABSTRACT

While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21(WAF1/Cip1), Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression.


Subject(s)
Interferon Regulatory Factors/metabolism , Keratinocytes/physiology , Receptor, Notch1/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Cycle Proteins/metabolism , Cell Differentiation , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p21/physiology , DNA-Binding Proteins/metabolism , ErbB Receptors/biosynthesis , ErbB Receptors/genetics , Genes, Tumor Suppressor , Homeodomain Proteins/metabolism , Humans , Interferon Regulatory Factors/biosynthesis , Interferon Regulatory Factors/genetics , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Oncogene Protein p21(ras)/metabolism , Promoter Regions, Genetic , RNA Interference , RNA, Small Interfering , Receptor, Notch1/genetics , Signal Transduction , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Transcription Factor HES-1
4.
Expert Opin Ther Targets ; 14(5): 541-52, 2010 May.
Article in English | MEDLINE | ID: mdl-20392166

ABSTRACT

IMPORTANCE OF THE FIELD: With some 220,000 new cases/year in the world, pancreatic adenocarcinoma is the fourth highest cause of death by cancers. Among newly diagnosed patients about 210,000 will die within 9 months following diagnosis. Therefore, effective adjuncts to current treatment strategies are necessary. Because embryological signaling pathways are upregulated in pancreatic adenocarcinoma, they represent potential targets for future therapies. AREAS COVERED IN THIS REVIEW: Our aim is to present the Notch pathway, and to describe its involvement in pancreatic pathophysiology/carcinogenesis. This pathway appeared as a prime target for pancreatic cancer therapy. In the light of the crosstalk of Notch with other survival/embryologic pathways, drugs affecting more than one pathway may have to be combined. WHAT THE READER WILL GAIN: Drugs against gamma-secretases could thus serve in cancer treatment and can be combined with drugs targeting survival pathways interplaying with Notch such as Hedgehog. TAKE HOME MESSAGE: Downregulation of Notch contributes to the inhibition and apoptosis of pancreatic cancer cells whereas Hedgehog inhibition will allow for enhanced delivery of drugs to the tumor. Both pathway inhibitors appear to have synergistic effects for future therapeutics for pancreatic adenocarcinoma, once safety issues of compounds are overcome.


Subject(s)
Pancreatic Neoplasms/metabolism , Receptors, Notch/metabolism , Signal Transduction , Humans , Oncogenes , Pancreatic Neoplasms/physiopathology
5.
Thyroid ; 20(2): 195-203, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20151827

ABSTRACT

BACKGROUND: Resveratrol, a polyphenol found in grapes, exhibits several beneficial health effects by its antioxidant, antiinflammatory, and chemopreventive properties. The aim of the present study was to determine the effect of resveratrol on iodide trapping and efflux as well as its mode of action using FRTL-5 cells, having in mind the pivotal role of the natrium iodide symporter (NIS) in the treatment of differentiated thyroid cancers. METHODS: Cells were treated with resveratrol for various times and doses, in the presence or absence of thyrotropin (TSH). Iodide trapping, iodide efflux, rat NIS (rNIS) protein expression, and cyclic AMP (cAMP) production were evaluated. RESULTS: Resveratrol increased iodide trapping in a time-dependent (optimal 6 hours) and dose-dependent (100 microM) way in the presence of TSH. It showed an additive effect when concomitantly added with an optimal dose of TSH. Resveratrol (50 microM) increased (threefold) rNIS protein expression. In TSH-deprived cells, resveratrol also provoked an increase in rNIS protein (>3-fold in 6 hours) with an optimum at 40 microM. Resveratrol did not inhibit iodide efflux from FRTL-5 cells. It neither increased intracellular cAMP nor induced the arborization of living cells, two TSH-induced effects. A non-cAMP mode of action is highly suspected. CONCLUSIONS: Resveratrol increases iodide trapping in FRTL-5 cells, increasing iodide influx and rNIS protein level even in the absence of TSH. It has an additive effect with TSH. Consequently, resveratrol could be a promising molecule for radioiodide therapy in follicular and papillary differentiated thyroid carcinoma in association with recombinant human TSH.


Subject(s)
Iodides/metabolism , Stilbenes/pharmacology , Symporters/biosynthesis , Thyroid Gland/metabolism , Animals , Cell Line , Cyclic AMP/biosynthesis , Dose-Response Relationship, Drug , Rats , Resveratrol , Stilbenes/administration & dosage , Thyroid Gland/drug effects , Thyrotropin/pharmacology
6.
Arch Biochem Biophys ; 495(1): 56-61, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20035708

ABSTRACT

Lipopolysaccharides (LPS) are major components of the cell wall of Gram negative bacteria implicated in the pathogenesis of bacterial infection. Resveratrol is a polyphenolic phytoalexin exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effects of this natural compound on LPS-induced proinflammatory effect using non-myeloid AR42J pancreatic cells. We found that LPS dose-dependently increased extracellular malondialdehyde (MDA) and nitric oxide without affecting their intracellular level whereas resveratrol abolished all these deleterious effects. LPS increased CD14 expression; IRAK1 and a phosphorylated form of p38 MAPK protein. Resveratrol counteracted LPS effect by decreasing CD14 and IRAK1 expression but unexpectedly increased the p38 MAPK protein phosphorylation. Altogether, our data highlighted the functionality of the TLR4-Myd88 signaling pathway in LPS pro-oxidant effect using non-myeloid cells. They further suggested that resveratrol exerted antioxidant properties either by a Myd88-dependent way not involving IRAK1 or by a TRIF dependent pathway.


Subject(s)
Antioxidants/pharmacology , Lipid Peroxidation/drug effects , Lipopolysaccharides/pharmacology , Stilbenes/pharmacology , Animals , Cell Line , Gene Expression Regulation/drug effects , Interleukin-1 Receptor-Associated Kinases/genetics , Interleukin-1 Receptor-Associated Kinases/metabolism , Lipopolysaccharide Receptors/genetics , Lipopolysaccharide Receptors/metabolism , Malondialdehyde/metabolism , Nitric Oxide/metabolism , Pancreas/cytology , Pancreas/drug effects , Rats , Resveratrol , Signal Transduction/drug effects , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Int J Cancer ; 125(5): 1016-26, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19405120

ABSTRACT

We previously reported that exosomal nanoparticles secreted by human pancreatic tumoral cell lines decrease tumoral cell proliferation through the mitochondria-dependent apoptotic pathway, because of activation of pro-apoptotic phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and of glucose synthase kinase-3beta (GSK-3beta). Interactions between exosomal nanoparticles and cells are thought to involve membrane lipid rafts. However, the underlying mechanism is unknown. Here, we report that the interaction of exosomal nanoparticles with pancreatic cancer cells led to decreased expression of hairy and enhancer-of-split homolog-1 (Hes-1), the intranuclear target of Notch-1 signaling pathway, and to activation of the apoptotic pathway after a cell cycle arrest in G(0)G(1) phase. Strikingly, the expression level of Notch-1 pathway components was critical, because exosomal nanoparticles decreased the proliferation of cells in which these partners are either weakly represented, in differentiated adenocarcinoma cells, or inhibited, in poorly differentiated carcinoma cells, by blocking presenilin in the gamma-secretase complex that regulates the Notch-1 pathway. Overexpression of Notch-1 intracellular domain resulted in the reversion of the cell proliferation inhibition promoted by exosomal nanoparticles. Blocking presenilin unexpectedly resulted in activation of PTEN and GSK-3beta. Conversely, inhibiting either PTEN or GSK-3beta increased Hes-1 expression and partially counteracted the inhibition of proliferation promoted by exosomal nanoparticles, highlighting reciprocal regulations between Notch signaling and PTEN/GSK-3beta. We concluded that interactions of exosomal nanoparticles with target cells, at lipid rafts where Notch-1 pathway partners are localized, hampered the functioning of the Notch-1 survival pathway and activated the apoptotic pathway, which determines tumoral cell fate.


Subject(s)
Adenocarcinoma/pathology , Apoptosis , Exosomes/metabolism , Nanoparticles , Pancreatic Neoplasms/pathology , Receptors, Notch/physiology , Adenocarcinoma/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Blotting, Western , Carbamates/pharmacology , Caspase 3/metabolism , Cell Differentiation , Cell Proliferation , Dipeptides/pharmacology , Flow Cytometry , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Mitochondria/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Pancreatic Neoplasms/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor HES-1 , Tumor Cells, Cultured
8.
Cancer Res ; 69(3): 802-9, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19176384

ABSTRACT

Aggressive melanoma cells can engage in a process termed vasculogenic mimicry (VM) that reflects the ability of tumor cells to express a multipotent, stem cell-like phenotype. Melanoma cell plasticity contributes to the lack of efficient therapeutic strategies targeting metastatic tumors. This study reveals cyclic AMP as a mediator of VM in vitro. In uveal and cutaneous metastatic aggressive human melanoma cells, an increase in cyclic AMP by forskolin, dibutyryl cyclic AMP, or G protein-coupled receptor (GPCR) ligands such as adrenaline and vasoactive intestinal peptide inhibited VM to different extents. Although chemical modulators of protein kinase A (PKA) had no effect, a specific pharmacologic activator of Exchange protein directly activated by cyclic AMP (Epac) impaired VM. Ras-associated protein-1 (Rap1) activation assays revealed that cyclic AMP-elevating agents induce a PKA-independent activation of Epac/Rap1. Pharmacologic inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished VM. Phosphorylation of ERK1/2 was PKA-independently inhibited by forskolin but not inhibited by Epac/Rap1 signaling, PKA modulation, or GPCR ligands. Furthermore, the forskolin also inhibited phosphatidyl inositol-3-kinase (PI3K)-mediated activation of protein kinase Akt, as monitored by Ser473 phosphorylation. The pharmacologic activation of Epac and GPCR ligands slightly stimulated Akt, a likely concomitant process of VM modulation. Collectively, these data show that forskolin strongly inhibits VM through PKA-independent activation of Epac/Rap1, PKA-, and Epac-independent inactivation of ERK1/2 and inhibition of PI3K/Akt. The data also show that VM inhibition by GPCR ligands involves mainly the Epac/Rap1-activated signal. Thus cyclic AMP inhibits VM through multiple signaling pathways.


Subject(s)
Cyclic AMP/metabolism , Melanoma/metabolism , Melanoma/pathology , 1-Methyl-3-isobutylxanthine/pharmacology , Cell Line, Tumor , Colforsin/pharmacology , Guanine Nucleotide Exchange Factors/metabolism , Humans , Ligands , MAP Kinase Signaling System/drug effects , Melanoma/blood supply , Microvessels/drug effects , Microvessels/metabolism , Microvessels/pathology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, G-Protein-Coupled/metabolism , Shelterin Complex , Signal Transduction/drug effects , Telomere-Binding Proteins/metabolism , Vasoactive Intestinal Peptide/pharmacology , alpha-MSH/pharmacology
9.
FASEB J ; 22(9): 3358-69, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18511551

ABSTRACT

Exosomes are vesicles secreted by most hematopoietic cells on fusion of multivesicular endosomes with the plasma membrane. Many studies have reported that exosomes may also be released by tumor cells. Exosomes are believed to play an antitumor role through immune cells. We asked whether tumor exosomes have biological activities on tumor cells. We report that human pancreatic tumor nanoparticles, exosome-like as characterized by proteomic analyses and rich in lipid rafts, decreased tumor cell proliferation. Nanoparticles increased Bax and decreased Bcl-2 expressions. Caspase-3 and -9 but not caspase-8 inhibitors impaired apoptosis, which implicates the mitochondria apoptotic pathway. The ceramide-sphingomyelin apoptotic pathway was inoperative. Moreover, nanoparticles induced phosphatase and tensin homolog (PTEN) and glycogen synthase kinase (GSK) -3beta activation and decreased pyruvate dehydrogenase activity. In nanoparticle-treated cells, PTEN formed complexes with actin, beta-catenin, and GSK-3beta. Thus, beta-catenin may no longer be available to activate the survival pathway. Nanoparticles triggered the down-regulation of cyclin D1 and poly(ADP-ribose) polymerase. Hence, nanoparticles counteracted the constitutively activated phosphatidylinositol 3-kinase/Akt survival pathway to drive tumor cells toward apoptosis. Our study provides the first evidence of an apoptotic function of tumor-derived nanoparticles on tumor cells. We propose a new role for nanoparticles, i.e., as signal carriers for interaction between cells, which may have implications in physiopathological situations.


Subject(s)
Apoptosis/drug effects , Membrane Microdomains , Nanoparticles , Pancreatic Neoplasms/pathology , Caspase Inhibitors , Cell Line, Tumor , Ceramides/physiology , Endosomes/physiology , Glycogen Synthase Kinase 3/physiology , Glycogen Synthase Kinase 3 beta , Humans , Lipids/analysis , Membrane Microdomains/physiology , Neoplasm Proteins/analysis , PTEN Phosphohydrolase/metabolism , Pancreatic Neoplasms/physiopathology , Phosphatidylinositol 3-Kinases/physiology , Poly(ADP-ribose) Polymerases/metabolism , Proto-Oncogene Proteins c-akt/physiology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Pyruvate Dehydrogenase Complex/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , bcl-2-Associated X Protein/biosynthesis
10.
Biochim Biophys Acta ; 1736(1): 67-76, 2005 Sep 05.
Article in English | MEDLINE | ID: mdl-16099206

ABSTRACT

The relationship between cholesterol and atherosclerosis has gained wide credence and red wine polyphenols have been shown to have an anti-atherogenic activity. In the present in vitro studies, we have evaluated and compared the effects of resveratrol, an active compound of red wine, and of a whole red wine polyphenolic extract (RWE) on the pancreatic bile salt-dependent lipase (BSDL). BSDL is involved in the duodenal hydrolysis of lipid esters and in part of cholesteryl esters thus favoring the bioavailability of free cholesterol. Resveratrol and RWE decrease the human and rat enzyme activities. Resveratrol and RWE also impaired the secretion of BSDL by the rat pancreatic AR4-2J cells used as secreting model. This effect is reversed by the removal of resveratrol or RWE from the cell culture medium. Further, resveratrol (but not RWE) affects the transcription of the gene encoding BSDL and dramatically diminishes the quantity of the enzyme that is expressed and secreted by AR4-2J cells. Results suggest that the hypolipemic effects of red wine polyphenols could partly originate from the inhibition of BSDL activity and secretion in the duodenum. In vivo, these effects could decrease the hydrolysis of dietary lipid esters and likely the absorption of free cholesterol.


Subject(s)
Flavonoids/physiology , Pancreas/enzymology , Sterol Esterase/metabolism , Animals , Cell Line, Tumor , Humans , Pancreas/drug effects , Pancreas/metabolism , Phenols , Polyphenols , RNA, Messenger/metabolism , Rats , Resveratrol , Sterol Esterase/biosynthesis , Sterol Esterase/genetics , Stilbenes/pharmacology , Wine , alpha-Amylases/metabolism
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