DOCSLIB.ORG

Identification of a DNA Methylation Signature in CD133+ Liver Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of a DNA Methylation Signature in CD133+ Liver Cancer Identification of a DNA methylation signature in CD133+ liver cancer cell lines and its relation with the transforming growth factor beta signaling pathway Marion Martin To cite this version: Marion Martin. Identification of a DNA methylation signature in CD133+ liver cancer cell lines and its relation with the transforming growth factor beta signaling pathway. Cancer. Ecole normale supérieure de lyon - ENS LYON, 2013. English. NNT : 2013ENSL0862. tel-00942762 HAL Id: tel-00942762 https://tel.archives-ouvertes.fr/tel-00942762 Submitted on 6 Feb 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE en vue de l'obtention du grade de Docteur de l’Université de Lyon, délivré par l’École Normale Supérieure de Lyon Discipline : Sciences de la Vie Laboratoire : Centre Internationale de la Recherche sur le Cancer – Groupe Epigénétique École Doctorale Biologie Moléculaire, Intégrative et Cellulaire ED 340 présentée et soutenue publiquement le 6 décembre 2013 par Madame Marion ESSIG épouse MARTIN Analyse de la méthylation de l'ADN des cellules CD133+ dans le cancer du foie et son interaction avec la voie de signalisation TGF-b Directeur de thèse : Dr Zdenko HERCEG Après l'avis de : Dr Jorg TOST Dr Ilaria MALANCHI Devant la commission d'examen formée de : Dr Pierre-Antoine DEFOSSEZ (examinateur) Pr Christine DELPRAT (Présidente du Jury) Dr Zdenko HERCEG (Directeur de thèse) Dr Ilaria MALANCHI (Rapportrice) Dr Jorg TOST (Rapporteur) 2 2 A Jérôme, Gaëlle, Bertie et les futures petites crapules qui suivront A Papipe 3 3 4 4 Remerciements Au Professeur Christine Delprat, pour avoir immédiatement accepté de faire partie de mon jury, de le présider et pour avoir pris le temps de discuter de mon travail. To Dr Tost and Dr Malanchi thank you for having accepted without any hesitations to be part of my jury, and for taking the time to review and discuss with me about my project. Au Dr Pierre-Antoine Defossez pour avoir accepté non seulement d'examiner mon travail mais également pour avoir pris le temps il y a 6 ans de me faire découvrir l'épigénétique. Je garde un vraiment bon souvenir de ce tout premier stage. To Dr Zdenko Herceg, thank you for having accepted me in the EGE team first for my master and then as a PhD student. I really enjoyed the 4 years that I spend in the epigenetic group not only at a professional level (with all the discussions during labmeetings and seminars that helped me to move my research forward) but also at personal level with all the outings, diners and coffee breaks. These 4 years in the same team have been a great first professional experience where I did not only learn how to work but where I also had the chance to create warm relationships with my colleagues. Un grand merci à Cyrille et Marie-Pierre, vous faites vraiment partie des piliers de ce groupe et grâce à votre accueil, vos conseils et au temps que vous avez pris pour moi j’ai pu au mieux m’intégrer dans l’équipe. Vous permettez réellement aux gens de travailler dans de meilleures conditions. Mais surtout merci pour votre bonne humeur et votre humour permanents, je vais vraiment regretter de ne plus avoir nos conversations et nos échanges de trouvailles sur internet. Par contre je suis réellement désolée d’avoir été une meilleure élève pour la nomenclature des primers que pour celle des différents tournois de foot… To Hector, I remember the first day when I arrived, you immediately took me in charge and you never let me down since. Beside the fact that you made me enter into the really selective and small world of “CSC believers”, your supervision has been a wonderful driving energy for my research. I know that you always say that you hate to teach, but at the end you really took the time to teach me how to conduct a scientific project. Thanks to you, I could use these 4 years to evolve and to improve my way to think and to work. Of course an important part of your supervision was the relaxing time, with beers at flannigan’s, the quiz, the bowlings, wii party etc … it was really nice also to be able to not only talk about science and to have fun outside the lab. Aux autres thésards du labo. Tout d’abord les “anciennes”: Marie-Pierre, Maria et Sheila. Au delà du fait que je pense qu’on a formé un bon quatuor faisant parfois perdre un peu la tête à Hector durant nos SS meetings, j’ai beaucoup appris à vos cotés et toujours été bien contente de trouver vos conseils pour survivre à la thèse ! Sheila ton amitié a été un vrai cadeau durant ton séjour en France. Nos discussions plus ou moins sérieuses, nos “enquêtes”, nos fous-rires, nos sorties ... mais à tes cotés j’ai aussi découvert une nouvelle culture et même quelques mots dans une nouvelle langue. Même si maintenant on est éloignées géographiquement, je sais qu’on repartagera d’autres super moments, qu’on refera des concours de bières, et qu’on s’échangera de nouveaux potins ;-) Eu gosta de voce muito minha tosquinha! Pedro t'as assuré en temps que co-thésard ;-). Merci de m'avoir fait rire, d'avoir potiné avec moi, d'avoir longuement disserté sur les différents menus macdo mais aussi d'avoir supporté mon (léger) 5 5 stress et mes (petites) sautes d'humeur. Je suis désolée de t'avoir transmis ma façon de ranger un bureau et de t'avoir entrainé dans les histoires de TGFbeta (même si je pense que ça t'a fait du bien de changer un peu de sujet parce que sinon en 3 ans t'aurais quand même pas glandé grand chose). Je te souhaite bon courage pour la suite et j’espère vraiment qu’on restera en contact. A Davide et Akram pour votre soutien. Vous avez été comme des grands-frères pendant la fin de cette thèse avec vos encouragements, vos compliments (Akram, ça va me manquer de ne plus me faire accueillir le matin par un “bonjour princesse”) et vos conseils. Davide je te remercie en particulier pour le temps que tu as pris pour m’aider à améliorer mon manuscript de thèse, je pense qu’au final tu seras une des rares personnes à l’avoir lu intégralement. Je remercie également les autres post-docs Reetta, Sri, Thai, Nawapol, Nasko, Sunny, Karen pour la bonne ambiance à laquelle ils ont contribués et les conseils qu'ils ont pu m'apporter. Merci, Sid, outre le fait que tu es une extraordinaire secrétaire toujours prête à se plier en 4 pour nous aider, tu as toujours eu un sourire et un petit mot gentil pour nous aider à bien démarrer la journée. Aux petites nouvelles Léa et Nora quelque soit la durée de votre passage, j’espère que vous apprécierez le temps passé chez EGE autant que moi. Aux Drs Philippe Merle et André Verdel, membres de mon comité de thèse. Vous avez su pendant nos réunions m'aider à faire murir ma discussion. Aux stagiaires que j'ai encadré complètement ou partiellement, Laetitia, Jihed et Roméo. Merci d'avoir essuyé les plâtres de ma supervision. De mon coté cette partie plus en lien avec l'enseignement a été un vrai plaisir durant ma thèse. A tout ceux que j'ai croisé dans les couloirs et les différents étages du CIRC, en particulier Thomas, Carla, Nino, Vladimir, Anupam, Clément, Maha, Djamel, Natalia et Stéphanie Bien sûr cette thèse n’est pas seulement le fruit d’une bonne relation et de collaboration avec mes collègues, la présence de tous mes amis et de toute ma famille a été plus que nécéssaire durant toutes ces années. A mes parents tout d’abord. Soutenir une thèse en biologie, ce n’était pas gagné avec mes 8/20 en terminale, et pourtant vous m’avez toujours fait confiance. Même si mon travail est resté je pense très flou pour vous, vous vous êtes toujours montrés intéressés par ce que je faisais et m’avez soutenu tout le long (bien sûr je ne parle pas que des armoires à gateaux remplies avant les concours, mais quand même ça a beaucoup joué ;-)). Je vous remercie également d’avoir toujours respecté et soutenu mes choix et jusqu’à présent je n’en ai regretté aucun. J’ai la chance de pouvoir continuer à choisir ce que je veux faire après ma thèse, donc Papa ne t’en fais pas je pense que tout ira bien ;-) reste juste aussi présent que tu l’as été jusqu’à maintenant. A mes frères et ma soeur, Agathe, Paul, Antoine, et Nicolas. Je sais que parfois on vous rabâche un peu trop que j’ai tout fait bien, que j’ai eu un parcours exemplaire. Mon parcours est pourtant semé de petites erreurs, de doutes, mais au final je ne le regrette pas. Ne regardez pas trop en détails ce que j’ai fait, mais concentrez vous plutôt sur vous pour trouver et construire votre propre chemin, celui qui vous ressemblera, qui ne sera surement pas parfait mais qui vous rendra fiers de vous.
Load more

Recommended publications
  • Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
    cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization.
    [Show full text]
  • 1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
    Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.
    [Show full text]
  • Open Full Page
    Published OnlineFirst January 12, 2016; DOI: 10.1158/0008-5472.CAN-15-1859 Cancer Tumor and Stem Cell Biology Research Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1a and HIF2a Desir ee Schonenberger€ 1, Sabine Harlander1,2, Michal Rajski1, Robert A. Jacobs1,2,3, Anne-Kristine Lundby1,2, Mojca Adlesic1, Tomas Hejhal1, Peter J. Wild4, Carsten Lundby1,2, and Ian J. Frew1,2 Abstract The von Hippel–Lindau (VHL) tumor suppressor gene is inac- chondrial abundance and oxidative capacity, glycogen accu- tivated in the majority of clear cell renal cell carcinomas (ccRCC), mulation, and acquisition of a clear cell phenotype in Vhl- but genetic ablation of Vhl alone in mouse models is insufficient deficient renal epithelial cells. HIF1a, but not HIF2a, induced to recapitulate human tumorigenesis. One function of pVHL is to Warburg-like metabolism characterized by increased glycoly- regulate the stability of the hypoxia-inducible factors (HIF), sis, decreased oxygen consumption, and decreased ATP pro- which become constitutively activated in the absence of pVHL. duction in mouse embryonic fibroblasts, providing insights In established ccRCC, HIF1a has been implicated as a renal tumor into the cellular changes potentially occurring in Vhl mutant suppressor, whereas HIF2a is considered an oncoprotein. In this renal cells before ccRCC formation. Importantly, deletion of study, we investigated the contributions of HIF1a and HIF2a to either Hif1a or Hif2a completely prevented the formation of ccRCC initiation in the context of Vhl deficiency. We found that renal cysts and tumors in Vhl/Trp53 mutant mice. These find- deleting Vhl plus Hif1a or Hif2a specifically in the renal ings argue that both HIF1a and HIF2a exert protumorigenic epithelium did not induce tumor formation.
    [Show full text]
  • Mir-17-92 Fine-Tunes MYC Expression and Function to Ensure
    ARTICLE Received 31 Mar 2015 | Accepted 22 Sep 2015 | Published 10 Nov 2015 DOI: 10.1038/ncomms9725 OPEN miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth Marija Mihailovich1, Michael Bremang1, Valeria Spadotto1, Daniele Musiani1, Elena Vitale1, Gabriele Varano2,w, Federico Zambelli3, Francesco M. Mancuso1,w, David A. Cairns1,w, Giulio Pavesi3, Stefano Casola2 & Tiziana Bonaldi1 The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c- MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 30 UTR shortening at different stages of tumorigenesis. 1 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy. 2 Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Molecular Genetics in Neuroblastoma Prognosis
    children Review Molecular Genetics in Neuroblastoma Prognosis Margherita Lerone 1, Marzia Ognibene 1 , Annalisa Pezzolo 2 , Giuseppe Martucciello 3,4 , Federico Zara 1,4, Martina Morini 5,*,† and Katia Mazzocco 6,† 1 Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] (M.L.); [email protected] (M.O.); [email protected] (F.Z.) 2 IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] 3 Department of Pediatric Surgery, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] 4 Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, University of Genova, 16132 Genova, Italy 5 Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy 6 Department of Pathology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-010-5636-2633 † Authors share senior authorship. Abstract: In recent years, much research has been carried out to identify the biological and genetic characteristics of the neuroblastoma (NB) tumor in order to precisely define the prognostic subgroups for improving treatment stratification. This review will describe the major genetic features and the recent scientific advances, focusing on their impact on diagnosis, prognosis, and therapeutic solutions in NB clinical management. Keywords: neuroblastoma; genetics; TRK; liquid biopsy; exosomes; telomere maintenance; hypoxia Citation: Lerone, M.; Ognibene, M.; Pezzolo, A.; Martucciello, G.; Zara, F.; 1. Introduction Morini, M.; Mazzocco, K. Molecular Genetics in Neuroblastoma Prognosis. Neuroblastoma (NB) is a pediatric heterogeneous disease with a median age of Children 2021, 8, 456. https:// 17 months at diagnosis, which can evolve with a benign course or fatal illness, with a doi.org/10.3390/children8060456 natural history ranging from a benign course to a terminal illness [1–3].
    [Show full text]
  • Β-Catenin Signaling Dynamics Regulate Cell Fate in Differentiating Neural Stem Cells
    β-Catenin signaling dynamics regulate cell fate in differentiating neural stem cells Alyssa B. Rosenblooma, Marcin Tarczynski a, Nora Lama, Ravi S. Kaneb,1, Lukasz J. Bugaja,c,1, and David V. Schaffera,d,e,f,1 aDepartment of Bioengineering, University of California, Berkeley, CA 94720; bSchool of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332; cDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104; dDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720; eDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and fHelen Wills Neuroscience Institute, University of California, Berkeley, CA 94720 Edited by Randall T. Moon, University of Washington, Seattle, WA, and approved September 21, 2020 (received for review May 4, 2020) Stem cells undergo differentiation in complex and dynamic environ- of how signaling dynamics impact cellular function. Optogenetics ments wherein instructive signals fluctuate on various timescales. has recently emerged as a field in which light—which can readily Thus, cells must be equipped to properly respond to the timing of be varied in intensity, space, and time—is harnessed to precisely signals, for example, to distinguish sustained signaling from transient modulate cell-signaling pathways. In this approach, light-sensitive noise. However, how stem cells respond to dynamic variations in proteins are engineered to interface with specific signaling path- differentiation cues is not well characterized. Here, we use optoge- ways, and the subsequent introduction of such an optogenetic netic activation of β-catenin signaling to probe the dynamic responses construct into cells renders the signaling pathway responsive to of differentiating adult neural stem cells (NSCs).
    [Show full text]
  • Single-Cell Analysis Uncovers Fibroblast Heterogeneity
    ARTICLE https://doi.org/10.1038/s41467-020-17740-1 OPEN Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination ✉ Lars Muhl 1,2 , Guillem Genové 1,2, Stefanos Leptidis 1,2, Jianping Liu 1,2, Liqun He3,4, Giuseppe Mocci1,2, Ying Sun4, Sonja Gustafsson1,2, Byambajav Buyandelger1,2, Indira V. Chivukula1,2, Åsa Segerstolpe1,2,5, Elisabeth Raschperger1,2, Emil M. Hansson1,2, Johan L. M. Björkegren 1,2,6, Xiao-Rong Peng7, ✉ Michael Vanlandewijck1,2,4, Urban Lendahl1,8 & Christer Betsholtz 1,2,4 1234567890():,; Many important cell types in adult vertebrates have a mesenchymal origin, including fibro- blasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes. 1 Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Blickagången 6, SE-14157 Huddinge, Sweden.
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • Proteomic Signatures of Brain Regions Affected by Tau Pathology in Early and Late Stages of Alzheimer's Disease
    Neurobiology of Disease 130 (2019) 104509 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Proteomic signatures of brain regions affected by tau pathology in early and T late stages of Alzheimer's disease Clarissa Ferolla Mendonçaa,b, Magdalena Kurasc, Fábio César Sousa Nogueiraa,d, Indira Plác, Tibor Hortobágyie,f,g, László Csibae,h, Miklós Palkovitsi, Éva Renneri, Péter Dömej,k, ⁎ ⁎ György Marko-Vargac, Gilberto B. Domonta, , Melinda Rezelic, a Proteomics Unit, Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil b Gladstone Institute of Neurological Disease, San Francisco, USA c Division of Clinical Protein Science & Imaging, Department of Clinical Sciences (Lund) and Department of Biomedical Engineering, Lund University, Lund, Sweden d Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil e MTA-DE Cerebrovascular and Neurodegenerative Research Group, University of Debrecen, Debrecen, Hungary f Institute of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary g Centre for Age-Related Medicine, SESAM, Stavanger University Hospital, Stavanger, Norway h Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary i SE-NAP – Human Brain Tissue Bank Microdissection Laboratory, Semmelweis University, Budapest, Hungary j Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary k National Institute of Psychiatry and Addictions, Nyírő Gyula Hospital, Budapest, Hungary ARTICLE INFO ABSTRACT Keywords: Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid β Alzheimer's disease peptide (Aβ) and tau protein are among the major pathological hallmarks of AD. Aβ and tau burden follows Proteomics predictable spatial patterns during the progression of AD.
    [Show full text]
  • A SARS-Cov-2 Protein Interaction Map Reveals Targets for Drug Repurposing
    Article A SARS-CoV-2 protein interaction map reveals targets for drug repurposing https://doi.org/10.1038/s41586-020-2286-9 A list of authors and affiliations appears at the end of the paper Received: 23 March 2020 Accepted: 22 April 2020 A newly described coronavirus named severe acute respiratory syndrome Published online: 30 April 2020 coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than Check for updates 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efcacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and eforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identifed the human proteins that physically associated with each of the SARS-CoV-2 proteins using afnity-purifcation mass spectrometry, identifying 332 high-confdence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors.
    [Show full text]
  • Data-Driven Discovery of Extravasation Pathway in Circulating Tumor Cells Received: 08 November 2016 S
    www.nature.com/scientificreports OPEN Data-Driven Discovery of Extravasation Pathway in Circulating Tumor Cells Received: 08 November 2016 S. Yadavalli1, S. Jayaram1,2, S. S. Manda1,3, A. K. Madugundu1,3, D. S. Nayakanti1, T. Z. Tan4, Accepted: 26 January 2017 R. Bhat5, A. Rangarajan5, A. Chatterjee1,6, H. Gowda1,6, J. P. Thiery4,7,8,9 & P. Kumar1 Published: 06 March 2017 Circulating tumor cells (CTCs) play a crucial role in cancer dissemination and provide a promising source of blood-based markers. Understanding the spectrum of transcriptional profiles of CTCs and their corresponding regulatory mechanisms will allow for a more robust analysis of CTC phenotypes. The current challenge in CTC research is the acquisition of useful clinical information from the multitude of high-throughput studies. To gain a deeper understanding of CTC heterogeneity and identify genes, pathways and processes that are consistently affected across tumors, we mined the literature for gene expression profiles in CTCs. Through in silico analysis and the integration of CTC-specific genes, we found highly significant biological mechanisms and regulatory processes acting in CTCs across various cancers, with a particular enrichment of the leukocyte extravasation pathway. This pathway appears to play a pivotal role in the migration of CTCs to distant metastatic sites. We find that CTCs from multiple cancers express both epithelial and mesenchymal markers in varying amounts, which is suggestive of dynamic and hybrid states along the epithelial-mesenchymal transition (EMT) spectrum. Targeting the specific molecular nodes to monitor disease and therapeutic control of CTCs in real time will likely improve the clinical management of cancer progression and metastases.
    [Show full text]