DOCSLIB.ORG

Non-Canonical WNT6/WNT10A Signal Factor Expression in EBV+ Post

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Teiken et al. Clin Sarcoma Res (2018) 8:10 https://doi.org/10.1186/s13569-018-0096-8 Clinical Sarcoma Research RESEARCH Open Access Non‑canonical WNT6/WNT10A signal factor expression in EBV post‑transplant smooth muscle tumors + Kristin Teiken1*†, Mark Kuehnel1†, Jan Rehkaemper2, Hans Kreipe1, Florian Laenger1, Kais Hussein1 and Danny Jonigk1 Abstract Post-transplant smooth muscle tumors (PTSMTs) are rare mesenchymal neoplasms which occur after solid organ or haematopoietic stem cell transplantation. PTSMT typically consist of Epstein–Barr-virus (EBV) smooth muscle-like cells and show an intermediate malignancy. Their main occurrences are visceral organs, especially+ the liver, but intrac- ranial appearances are described and associated with a poor prognosis. EBV drives the growth of PTSMT; however, the underlying molecular mechanisms still remain unclear. Gene expression analysis of a set of morphologically similar tumors (leiomyomas, leiomyosarcomas, angioleiomyomas and endothelial haemangiomas) from patients without immunosuppression or EBV-association was performed. Our fndings indicate that PTSMT’s growth is driven by two factors of the wingless-type protein family: WNT6 and WNT10A. We are frst to report that in PTSMTs, a non-canonical activation of WNT, independent of beta-catenin, drives tumor cell proliferation via MTOR/AKT1, MYC and Cyclin D2. Keywords: PTSMT, Post-transplant smooth muscle tumors, Angioleiomyomas, EBV, WNT Background patients [5]) but represent an important clinical and radi- Tumors with predominant or partial smooth muscle dif- ological diferential diagnosis in immune-compromised ferentiation make up a broad spectrum of mesenchymal patients, particularly to post-transplant lymphoprolifera- neoplasms. Most of these tumors are based on sponta- tive diseases (PTLD). In PTSMT, the site of manifesta- neous mutations of a mesenchymal stem cell. A rare and tion determines the patients’ outcome [2]. In particular, virus-associated entity are the post-transplant smooth cerebral PTSMT has a poor prognosis, while histological muscle tumors (PTSMT) [1, 2]. Tese tumors are typi- features (mitotic rate, cellular atypia, and necrosis) have cally positive for the Epstein–Barr virus (EBV) and can no prognostic impact [1]. manifest themselves at any time and in any organ after Epstein–Barr virus is specialized to infect B cells and transplantation [1]. Similar neoplasms can also occur almost all adults harbor a small population of EBV+ non- in any other immunosuppressive condition, in particu- neoplastic B cells, which are controlled by T cell homeo- lar after infection with human immunodefciency virus stasis. It is not known how EBV enters non-B cell tissues, (HIV; HIV-SMT) or congenital immune defects (CI- such as mesenchymal cells. It is thought that the PTSMT SMT) [1, 3, 4]. cell of origin is derived from a perivascular non-endothe- Post-transplant smooth muscle tumors are rare in lial mesenchymal smooth muscle stem cell. EBV+ regard to the total population (< 1% of transplanted PTSMT have a type III-like latency with expression of EBV protein EBNA (Epstein–Barr nuclear antigen) but often lack EBV latent membrane protein 1 (LMP1) *Correspondence: Teiken.Kristin@mh‑hannover.de expression [6]. Te tumorigenic role of EBV in smooth † Kristin Teiken and Mark Kuehnel contributed equally to this work muscle neoplasms is not clear because particularly HIV- 1 Institute of Pathology, Hannover Medical School (MHH), Carl‑Neuberg‑Str. 1, 30625 Hannover, Germany SMT can be EBV negative, indicating that the virus is not Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Teiken et al. Clin Sarcoma Res (2018) 8:10 Page 2 of 8 absolutely necessary for aberrant smooth muscle prolif- uncertain and aberrant myogenous venous wall cells eration [1]. are still under discussion as the cells of origin [2, 8]. In our previous works, we found a molecular microenvi- Before performing molecular analysis, the angioleio- ronment which is not related to EBV infection, but rather myomas were histologically sub grouped according to to smooth muscle diferentiation [5]. In addition, EBV is the old but current standard of Morimoto [9] (13/28 able to induce neoangiogenesis, but we found only minor capillary solid, 7/28 venous, 5/28 cavernous, 3/28 changes on the transcriptional level, including increased mixed capillary-cavernous). All samples of forma- levels of angiopoietin 2 (ANGPT2) [7]. Defning driver lin fixed and paraffin-embedded (FFPE) tumors were mutations in PTSMT are still not known. However, we selected from the archive of the Institutes of Pathology and others found up-regulation of MYC proto-oncogene in Muenster (12/28 angioleiomyomas) and Hannover transcripts, protein expression of phosphorylated mecha- (all other samples). nistic target of rapamycin kinase (MTOR) and phospho- rylated AKT serine/threonine kinase 1 (AKT1) signaling Transcript expression analysis factors [2, 6]. Samples contained > 80% tumor tissue and RNA was In the present analyses we wanted to asses if and which extracted and purifed with our established mineral oil transcript profle of mesenchymal stem cell and signaling method and RNeasy Mini Kit (Qiagen, Hilden, Ger- factors difer between PTSMT and other neoplasms with many) via Maxwell ® system (Promega cooperation, smooth muscle diferentiation. Mannheim, Germany). RNA was quantifed by Qubit® 2.0 fuorometer (Life Technologies/Termo Fisher Sci- Methods entifc, Waltham, MA, USA). Transcript expression Tumor samples analysis was performed via NanoString nCounter™ sys- EBV+ PTSMTs comprised six tumors from fve patients; tem. NanoString uses digital fuorescent reporters for one patient had a tumor in the spleen and another in a gene detection and enables analysis of small amount of cerebral sinus. We previously reported the clinical and RNA while minimizing background signals. We used histopathological characteristics of four of these patients the prefabricated stem cell panel (includes 193 target [2]. Te ffth patient was a female (age: 61 years) who genes and six endogenous control genes) as described developed a PTSMT in the liver 5 years after kidney in the manufacturer’s protocol (NanoString Technolo- transplantation (tumor diameter 3.1 cm, 10% Ki67, posi- gies, Seattle, WA, USA). Endogenous control genes were tive for EBV in situ hybridization (EBER), smooth muscle glucuronidase beta (GUSB), glyceraldehyde-3-phosphate actin, caldesmon and desmin). dehydrogenase (GAPDH), clathrin heavy chain (CLTC), For control purposes, the following tumors were hypoxanthine phosphoribosyltransferase 1 (HPRT1), analyzed (Table 1, Fig. 1): (i) smooth muscle tumors phosphoglycerate kinase 1 (PGK1) and tubulin beta class (nine visceral leiomyomas and four central venous I (TUBB). G1–2 leiomyosarcomas) and (ii) mixed smooth mus- cle and vascular tumors (28 with different histological Immunohistochemistry subtypes of angioleiomyomas). Additionally, we added Deparafnized and rehydrated FFPE tissue sections (iii) a vascular tumor control group (five endothelial (1–2 μm) were processed in an automated staining sys- haemangiomas), as the actual origin of PTSMT is still tem (Benchmark ULTRA, Ventana Medical Systems, Inc., Table 1 Sample set and clinical data Entities PTSMT Leiomyoma (LM) Leiomyosarcoma (LMS) Angioleiomyoma Endothelial haeman- (ALM) gioma (EHA) Number of n 6 (5 patients) n 9 n 4 n 28 n 5 tumors = = = = = Age (median, 11.5 (6–61) 60 (29–71) 63 (45–71) 60 (23–79) 48 (32–58) range) Gender ♀ 100% ♀ 89% ♀ 75% ♀ 64% ♀ 60% ♂ 0% ♂ 11% ♂ 25% ♂ 36% ♂ 40% Tumor localisation Kidney (n 2) Stomach (n 3) Pulmonary artery (n 2) Lower extremities Lower extremities (n 3) Lung (n = 1) Kidney (n =2) Right atrium (n 1) = (n 13) Head–Neck (n 1) = Colon (n= 1) Skin (n 2)= Adrenal gland vein= Upper= extremities (n 2) Mediastinal (n = 1) Spleen (n= 1) Esophagus= (n 1) (n 1) Head–Neck (n 3) = = = = = = Confuens sinuum (n 1) Mesenterium (n 1) Genital ♀ (n 2) = = Skin/soft tissue= (n 8) = Teiken et al. Clin Sarcoma Res (2018) 8:10 Page 3 of 8 Fig. 1 Histological appearance of the fve diferent entities. a Post transplant smooth muscle tumor (haematoxylin–eosin stain (HE stain, 100 ) × with inserted positive EBV-in situ hybridization (EBER), b visceral leiomyoma (HE stain, 100 ), c visceral leiomyosarcoma of the central venous tract × (right atrium, HE stain, 100 ) with prominent atypia and increased level of mitosis fgures, d endothelial haemangioma (HE stain, 100 ) with promi- × × nent vessels, e angioleiomyoma (HE stain, 50 ), in particular venous subtype with prominently walled vessels (arrows) × Tucson, AZ, USA). A monoclonal anti-beta-catenin anti- comparisons. P values < 0.05 were considered as statisti- body was used. cally signifcant. Heatmaps were generated using R. Data analysis Results Raw data of transcript target gene expression were ana- Increased WNT6/WNT10A levels in PTSMT lyzed by nSolver™ software (NanoString Technologies)
Recommended publications
  • Watsonjn2018.Pdf (1.780Mb)

    Watsonjn2018.Pdf (1.780Mb)

    UNIVERSITY OF CENTRAL OKLAHOMA Edmond, Oklahoma Department of Biology Investigating Differential Gene Expression in vivo of Cardiac Birth Defects in an Avian Model of Maternal Phenylketonuria A THESIS SUBMITTED TO THE GRADUATE FACULTY In partial fulfillment of the requirements For the degree of MASTER OF SCIENCE IN BIOLOGY By Jamie N. Watson Edmond, OK June 5, 2018 J. Watson/Dr. Nikki Seagraves ii J. Watson/Dr. Nikki Seagraves Acknowledgements It is difficult to articulate the amount of gratitude I have for the support and encouragement I have received throughout my master’s thesis. Many people have added value and support to my life during this time. I am thankful for the education, experience, and friendships I have gained at the University of Central Oklahoma. First, I would like to thank Dr. Nikki Seagraves for her mentorship and friendship. I lucked out when I met her. I have enjoyed working on this project and I am very thankful for her support. I would like thank Thomas Crane for his support and patience throughout my master’s degree. I would like to thank Dr. Shannon Conley for her continued mentorship and support. I would like to thank Liz Bullen and Dr. Eric Howard for their training and help on this project. I would like to thank Kristy Meyer for her friendship and help throughout graduate school. I would like to thank my committee members Dr. Robert Brennan and Dr. Lilian Chooback for their advisement on this project. Also, I would like to thank the biology faculty and staff. I would like to thank the Seagraves lab members: Jailene Canales, Kayley Pate, Mckayla Muse, Grace Thetford, Kody Harvey, Jordan Guffey, and Kayle Patatanian for their hard work and support.
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation

    Transcriptional Control of Tissue-Resident Memory T Cell Generation

    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
  • Loss of Tcf7 Diminishes Hematopoietic Stem&Sol

    Loss of Tcf7 Diminishes Hematopoietic Stem&Sol

    Letters to the Editor 1613 13 Ebert BL, Galili N, Tamayo P, Bosco J, Mak R, Pretz J et al. An erythroid differ- malignancies without del[5q] treated with lenalidomide. J Hematol Oncol 2012; entiation signature predicts response to lenalidomide in myelodysplastic syn- 5:4. drome. PLoS Med 2008; 5: e35. 15 Wei S, Chen X, McGraw K, Zhang L, Komrokji R, Clark J et al. Lenalidomide pro- 14 Sugimoto Y, Sekeres MA, Makishima H, Traina F, Visconte V, Jankowska A et al. motes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodys- Cytogenetic and molecular predictors of response in patients with myeloid plastic syndrome with chromosome 5q deletion. Oncogene 2013; 32: 1110–1120. Loss of Tcf 7 diminishes hematopoietic stem/progenitor cell function Leukemia (2013) 27, 1613–1614; doi:10.1038/leu.2012.354 BMC/HL %LSK The canonical Wnt-b-catenin pathway is an evolutionarily WT 5.0x107 0.24 conserved and tightly regulated pathway in development. Activation of this pathway occurs upon binding of a soluble Wnt Tcf7-/- 4.9x107 0.25 protein to a membrane-associated receptor, and leads to the disruption and inhibition of a protein complex responsible for the 10000 phosphorylation and breakdown of b-catenin. Inhibition of this so- WT called destruction complex, composed of the tumor suppressor Tcf7-/- Apc, the Ser-Thr kinases Gsk-3b and CK-I, and the scaffold and 1000 tumor suppressor protein Axin, results in stabilization and BM cells (nuclear) accumulation of b-catenin. Stabilized b-catenin forms a 6 bipartite transcription factor with the Tcf-Lef family of transcrip- 100 tion factors (including Tcf7, Tcf7l1, Tcf7l2 and Lef1) to activate a Wnt-controlled gene expression program.1 In the hematopoietic system, a role for Wnt signaling was 10 2 first demonstrated during T-cell development in the thymus.
  • Catenin Signaling Regulate External Genitalia Formation As an Appendic

    Catenin Signaling Regulate External Genitalia Formation As an Appendic

    RESEARCH ARTICLE 3969 Development 136, 3969-3978 (2009) doi:10.1242/dev.039438 Dosage-dependent hedgehog signals integrated with Wnt/-catenin signaling regulate external genitalia formation as an appendicular program Shinichi Miyagawa1,2, Anne Moon3,*, Ryuma Haraguchi2,*, Chie Inoue4, Masayo Harada1, Chiaki Nakahara4, Kentaro Suzuki1, Daisuke Matsumaru4, Takehito Kaneko2, Isao Matsuo5, Lei Yang6, Makoto M. Taketo7, Taisen Iguchi8, Sylvia M. Evans9 and Gen Yamada1,4,† Embryonic appendicular structures, such as the limb buds and the developing external genitalia, are suitable models with which to analyze the reciprocal interactions of growth factors in the regulation of outgrowth. Although several studies have evaluated the individual functions of different growth factors in appendicular growth, the coordinated function and integration of input from multiple signaling cascades is poorly understood. We demonstrate that a novel signaling cascade governs formation of the embryonic external genitalia [genital tubercle (GT)]. We show that the dosage of Shh signal is tightly associated with subsequent levels of Wnt/-catenin activity and the extent of external genitalia outgrowth. In Shh-null mouse embryos, both expression of Wnt ligands and Wnt/-catenin signaling activity are downregulated. -catenin gain-of-function mutation rescues defective GT outgrowth and Fgf8 expression in Shh-null embryos. These data indicate that Wnt/-catenin signaling in the distal urethral epithelium acts downstream of Shh signaling during GT outgrowth. The current data also suggest that Wnt/-catenin regulates Fgf8 expression via Lef/Tcf binding sites in a 3Ј conserved enhancer. Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among multiple Fgfs in GT development.
  • A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic Β-Cells

    A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic Β-Cells

    This is “Advance Publication Article” Kurume Medical Journal, 65, 00-00, 2018 Original Article A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic β-cells YAYOI KURITA, TSUYOSHI OHKI, ERI SOEJIMA, XIAOHONG YUAN, SATOMI KAKINO, NOBUHIKO WADA, TOSHIHIKO HASHINAGA, HITOMI NAKAYAMA, JUNICHI TANI, YUJI TAJIRI, YUJI HIROMATSU, KENTARO YAMADA* AND MASATOSHI NOMURA Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan, *Diabetes Center of Asakura Medical Association Hospital, Asakura 838-0069, Japan Received 12 February 2018, accepted 1 May 2018 J-STAGE advance publication 11 March 2019 Edited by MAKOTO TAKANO Summary: Aims/Introduction: Several lines of evidence suggest that dysregulation of the WNT signaling pathway is involved in the pathogenesis of type 2 diabetes. This study was performed to elucidate the effects of a high-fat/high-sucrose (HF/HS) diet on pancreatic islet functions in relation to modulation of WNT ligand expression in β-cells. Materials and Methods: Mice were fed either standard mouse chow or a HF/HS diet from 8 weeks of age. At 20 weeks of age, intraperitoneal glucose tolerance tests were performed in both groups of mice, followed by euthanasia and isolation of pancreatic islets. WNT-related gene expression in islets and MIN6 cells was measured by quantitative real-time RT-PCR. To explore the direct effects of WNT signals on pancreatic β-cells, MIN6 cells were exposed to recombinant mouse WNT4 protein (rmWNT4) for 48 h, and glucose-induced insulin secre- tion was measured. Furthermore, Wnt4 siRNAs were transfected into MIN6 cells, and cell viability and insulin secretion were measured in control and Wnt4 siRNA-transfected MIN6 cells.
  • WNT10A Gene Wnt Family Member 10A

    WNT10A Gene Wnt Family Member 10A

    WNT10A gene Wnt family member 10A Normal Function The WNT10A gene is part of a large family of WNT genes, which play critical roles in development starting before birth. These genes provide instructions for making proteins that participate in chemical signaling pathways in the body. Wnt signaling controls the activity of certain genes and regulates the interactions between cells during embryonic development. The protein produced from the WNT10A gene plays a role in the development of many parts of the body. It appears to be essential for the formation of tissues that arise from an embryonic cell layer called the ectoderm. These tissues include the skin, hair, nails, teeth, and sweat glands. Researchers believe that the WNT10A protein is particularly important for the formation and shaping of both baby (primary) teeth and adult ( permanent) teeth. Health Conditions Related to Genetic Changes Hypohidrotic ectodermal dysplasia Several mutations in the WNT10A gene have been found to cause hypohidrotic ectodermal dysplasia, the most common form of ectodermal dysplasia. Starting before birth, ectodermal dysplasias result in the abnormal development of the skin, hair, nails, teeth, and sweat glands. Hypohidrotic ectodermal dysplasia is characterized by a reduced ability to sweat (hypohidrosis), sparse scalp and body hair (hypotrichosis), and several missing teeth (hypodontia) or teeth that are malformed. WNT10A gene mutations account for about 5 percent of all cases of hypohidrotic ectodermal dysplasia. Most of the WNT10A gene mutations associated with hypohidrotic ectodermal dysplasia change single protein building blocks (amino acids) in the WNT10A protein, which impairs its function. The resulting shortage of functional WNT10A protein disrupts Wnt signaling during the development of ectodermal tissues, particularly the teeth.
  • Theranostics WNT6 Is a Novel Oncogenic Prognostic Biomarker In

    Theranostics WNT6 Is a Novel Oncogenic Prognostic Biomarker In

    Theranostics 2018, Vol. 8, Issue 17 4805 Ivyspring International Publisher Theranostics 2018; 8(17): 4805-4823. doi: 10.7150/thno.25025 Research Paper WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma Céline S. Gonçalves1,2, Joana Vieira de Castro1,2, Marta Pojo1,2, Eduarda P. Martins1,2, Sandro Queirós1,2, Emmanuel Chautard3,4, Ricardo Taipa5, Manuel Melo Pires5, Afonso A. Pinto6, Fernando Pardal7, Carlos Custódia8, Cláudia C. Faria8,9, Carlos Clara10, Rui M. Reis1,2,10, Nuno Sousa1,2, Bruno M. Costa1,2 1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal 2. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal 3. Université Clermont Auvergne, INSERM, U1240 IMoST, 63000 Clermont Ferrand, France 4. Pathology Department, Université Clermont Auvergne, Centre Jean Perrin, 63011 Clermont-Ferrand, France 5. Neuropathology Unit, Department of Neurosciences, Centro Hospitalar do Porto, Porto, Portugal 6. Department of Neurosurgery, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal 7. Department of Pathology, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal 8. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal 9. Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), Lisbon, Portugal 10. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos - S. Paulo, Brazil. Corresponding author: Bruno M. Costa, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal. Email: [email protected]; Phone: (+351)253604837; Fax: (+351)253604831 © Ivyspring International Publisher.
  • Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response

    Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response

    International Journal of Molecular Sciences Review Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response Casey D. Stefanski 1,2 and Jenifer R. Prosperi 1,2,3,* 1 Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46617, USA; [email protected] 2 Mike and Josie Harper Cancer Research Institute, South Bend, IN 46617, USA 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN 46617, USA * Correspondence: [email protected]; Tel.: +1-574-631-4002 Received: 30 September 2020; Accepted: 20 October 2020; Published: 22 October 2020 Abstract: Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients. While APC is commonly known for its role as a negative regulator of the WNT pathway, APC has numerous binding partners and functional roles. Through APC’s interactions with DNA repair proteins, DNA replication proteins, tubulin, and other components, recent evidence has shown that APC regulates the chemotherapy response in cancer cells. In this review article, we provide an overview of some of the cellular processes in which APC participates and how they impact chemoresistance through both epithelial- and TME-derived mechanisms. Keywords: adenomatous polyposis coli; chemoresistance; WNT signaling 1.
  • Hepatitis C Virus As a Unique Human Model Disease to Define

    Hepatitis C Virus As a Unique Human Model Disease to Define

    viruses Review Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection David Wolski and Georg M. Lauer * Liver Center at the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA * Correspondence: [email protected]; Tel.: +1-617-724-7515 Received: 27 June 2019; Accepted: 23 July 2019; Published: 26 July 2019 Abstract: The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses. Keywords: viral hepatitis; hepatitis C virus; T cells; transcriptional regulation; transcription factors; metabolism; nucleosome 1.
  • Accompanies CD8 T Cell Effector Function Global DNA Methylation

    Accompanies CD8 T Cell Effector Function Global DNA Methylation

    Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer, Benjamin G. Barwick, Benjamin A. Youngblood, Rafi Ahmed and Jeremy M. Boss This information is current as of October 1, 2021. J Immunol 2013; 191:3419-3429; Prepublished online 16 August 2013; doi: 10.4049/jimmunol.1301395 http://www.jimmunol.org/content/191/6/3419 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130139 Material 5.DC1 References This article cites 81 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/191/6/3419.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer,* Benjamin G. Barwick,* Benjamin A. Youngblood,*,† Rafi Ahmed,*,† and Jeremy M.
  • Deregulated Wnt/Β-Catenin Program in High-Risk Neuroblastomas Without

    Deregulated Wnt/Β-Catenin Program in High-Risk Neuroblastomas Without

    Oncogene (2008) 27, 1478–1488 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ONCOGENOMICS Deregulated Wnt/b-catenin program in high-risk neuroblastomas without MYCN amplification X Liu1, P Mazanek1, V Dam1, Q Wang1, H Zhao2, R Guo2, J Jagannathan1, A Cnaan2, JM Maris1,3 and MD Hogarty1,3 1Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA and 3Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Neuroblastoma (NB) is a frequently lethal tumor of Introduction childhood. MYCN amplification accounts for the aggres- sive phenotype in a subset while the majority have no Neuroblastoma (NB) is a childhood embryonal malig- consistently identified molecular aberration but frequently nancy arising in the peripheral sympathetic nervous express MYC at high levels. We hypothesized that acti- system. Half of all children with NB present with features vated Wnt/b-catenin (CTNNB1) signaling might account that define their tumorsashigh riskwith poor overall for this as MYC is a b-catenin transcriptional target and survival despite intensive therapy (Matthay et al., 1999). multiple embryonal and neural crest malignancies have A subset of these tumors are characterized by high-level oncogenic alterations in this pathway. NB cell lines without genomic amplification of the MYCN proto-oncogene MYCN amplification express higher levels of MYC and (Matthay et al., 1999) but the remainder have no b-catenin (with aberrant nuclear localization) than MYCN- consistently identified aberration to account for their amplified cell lines.
  • Towards an Integrated View of Wnt Signaling in Development Renée Van Amerongen and Roel Nusse*

    Towards an Integrated View of Wnt Signaling in Development Renée Van Amerongen and Roel Nusse*

    HYPOTHESIS 3205 Development 136, 3205-3214 (2009) doi:10.1242/dev.033910 Towards an integrated view of Wnt signaling in development Renée van Amerongen and Roel Nusse* Wnt signaling is crucial for embryonic development in all animal Notably, components at virtually every level of the Wnt signal species studied to date. The interaction between Wnt proteins transduction cascade have been shown to affect both β-catenin- and cell surface receptors can result in a variety of intracellular dependent and -independent responses, depending on the cellular responses. A key remaining question is how these specific context. As we discuss below, this holds true for the Wnt proteins responses take shape in the context of a complex, multicellular themselves, as well as for their receptors and some intracellular organism. Recent studies suggest that we have to revise some of messengers. Rather than concluding that these proteins are shared our most basic ideas about Wnt signal transduction. Rather than between pathways, we instead propose that it is the total net thinking about Wnt signaling in terms of distinct, linear, cellular balance of signals that ultimately determines the response of the signaling pathways, we propose a novel view that considers the receiving cell. In the context of an intact and developing integration of multiple, often simultaneous, inputs at the level organism, cells receive multiple, dynamic, often simultaneous and of both Wnt-receptor binding and the downstream, sometimes even conflicting inputs, all of which are integrated to intracellular response. elicit the appropriate cell behavior in response. As such, the different signaling pathways might thus be more intimately Introduction intertwined than previously envisioned.