Urogenital System
- PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice
- Marie Christou‐Kent1,
- Zine‐Eddine Kherraf1,
- Amir Amiri‐Yekta1,2,3,
- Emilie Le Blévec1,
- Thomas Karaouzène1,
- Béatrice Conne4,
- Jessica Escoffier1,
- Said Assou5,
- Audrey Guttin6,
- Emeline Lambert1,
- Guillaume Martinez1,2,7,
- Magalie Boguenet1,
- Selima Fourati Ben Mustapha8,
- Isabelle Cedrin Durnerin9,
- Lazhar Halouani8,
- Ouafi Marrakchi8,
- Mounir Makni8,
- Habib Latrous8,
- Mahmoud Kharouf8,
- Charles Coutton1,2,7,
- Nicolas Thierry‐Mieg10,
- Serge Nef4,
- Serge P Bottari1,
- Raoudha Zouari8,
- Jean Paul Issartel6,
- Pierre F Ray1,2,† and
- Christophe Arnoult (christophe.arnoult{at}univ-grenoble-alpes.fr)*,1,†
- 1Genetics, Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- 2UM GI‐DPI, CHU de Grenoble, Grenoble, France
- 3Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- 5IRMB, INSERM U1183, CHRU Montpellier, Université Montpellier, Montpellier, France
- 6Grenoble Neuroscience Institute, INSERM 1216, Université Grenoble Alpes, Grenoble, France
- 7UM de Génétique Chromosomique, CHU de Grenoble, Grenoble, France
- 8Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- 9Service de Médecine de la Reproduction, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique ‐ Hôpitaux de Paris, Bondy, France
- 10Univ. Grenoble Alpes/CNRS, TIMC‐IMAG CNRS UMR 5525, Grenoble, France
- ↵*Corresponding author. Tel: +33 476 637 408; E‐mail: christophe.arnoult{at}univ-grenoble-alpes.fr
↵† These authors contributed equally to this work as senior authors
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
Synopsis
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
In a cohort of 23 infertile women from North Africa with oocyte meiotic deficiency (OMD), a truncating mutation in the gene PATL2, encoding an RNA‐binding protein, was identified in 26% of patients.
Patl2 knockout female mice presented severe subfertility, confirming the human diagnostic. Patl2 knockout mouse oocytes could progress to the MII stage, however with numerous morphological defects hampering normal fertilisation and development.
Patl2 is not detectable in primordial follicle oocytes, but is strongly expressed during oocyte growth and remains detectable at least until the MII stage.
Patl2 has a unique expression pattern from primordial follicle‐stage to MII‐stage oocytes and did not colocalise with Cpeb1, Msy2 or Ddx6 known to stabilise mRNA during oocyte growth.
Patl2 deficiency leads to a down or up‐regulation of a subset of mRNAs encoding proteins which are crucial for oocyte meiotic progression and early embryonic development, with no effect on the GV‐MII transition.
EMBO Mol Med (2018) e8515
- Received September 21, 2017.
- Revision received March 12, 2018.
- Accepted March 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers
- Mélanie Mahe1,2,†,
- Florent Dufour1,2,†,
- Hélène Neyret‐Kahn1,2,
- Aura Moreno‐Vega1,2,
- Claire Beraud3,
- Mingjun Shi1,2,
- Imene Hamaidi4,
- Virginia Sanchez‐Quiles1,2,
- Clementine Krucker1,2,
- Marion Dorland‐Galliot1,2,
- Elodie Chapeaublanc1,2,
- Remy Nicolle1,2,
- Hervé Lang4,
- Celio Pouponnot5,6,7,
- Thierry Massfelder8,
- François Radvanyi1,2 and
- Isabelle Bernard‐Pierrot (isabelle.bernard-pierrot{at}curie.fr)*,1,2
- 1Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Paris, France
- 2CNRS, UMR144, Sorbonne Universités UPMC Université Paris 06, Paris, France
- 3UROLEAD SAS, School of Medicine, Strasbourg, France
- 4Department of Urology, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- 5Institut Curie, Orsay, France
- 6CNRS UMR3347 Centre Universitaire, Orsay, France
- 7INSERM U1021 Centre Universitaire, Orsay, France
- 8INSERM UMR_S1113, Section of Cell Signalization and Communication in Kidney and Prostate Cancer, School of Medicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM and University of Strasbourg, Strasbourg, France
- ↵*Corresponding author. Tel: +33 1 42 34 63 40; Fax: +33 1 42 34 63 49; E‐mail: isabelle.bernard-pierrot{at}curie.fr
↵† These authors contributed equally to this work
In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.
Synopsis
In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.
MYC is a key master regulator of proliferation activated by aberrantly activated FGFR3.
FGFR3‐dependent MYC accumulation is dependent on p38, which regulates MYC mRNA levels, and AKT, which stabilizes MYC protein.
FGFR3 is directly targeted by MYC.
Disrupting the FGFR3/MYC loop using FGFR3, p38, AKT, or BET bromodomain inhibitors decreases cell viability and tumor growth in FGFR3‐dependent cell lines.
Evidence for the relevance of the FGFR3/MYC feedback loop to human tumors is provided by the decrease in both FGFR3 and MYC levels induced by a pan‐FGFR inhibitor in a PDX model bearing an FGFR3 mutation, and by the positive correlation between MYC and FGFR3 levels in human tumors with FGFR3 mutations.
EMBO Mol Med (2018) 10: e8163
- Received June 15, 2017.
- Revision received January 19, 2018.
- Accepted January 23, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Identification of potential therapeutic targets in prostate cancer through a cross‐species approach
- Sarah Jurmeister (sarah{at}jurmeister.eu)*,1,†,
- Antonio Ramos‐Montoya1,†,
- Chiranjeevi Sandi1,
- Nelma Pértega‐Gomes2,
- Karan Wadhwa1,
- Alastair D Lamb1,3,4,
- Mark J Dunning5,
- Jan Attig6,7,
- Jason S Carroll8,
- Lee GD Fryer1,
- Sérgio L Felisbino9,† and
- David E Neal1,3,4,†
- 1Uro‐oncology Research Group, CRUK Cambridge Institute, Cambridge, UK
- 2Department of Medical Oncology, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- 3Department of Urology, University of Cambridge, Cambridge, UK
- 4Department of Oncology, Addenbrooke's Hospital, Cambridge, UK
- 5Bioinformatics Core Facility, CRUK Cambridge Institute, Cambridge, UK
- 6Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- 7MRC‐Laboratory of Molecular Biology, Cambridge, UK
- 8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- 9Department of Morphology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Sao Paulo, Brazil
- ↵*Corresponding author. Tel: +44 1223 943698; E‐mail: sarah{at}jurmeister.eu
↵† These authors contributed equally to this work
Genetically engineered mouse models (GEMM) of human cancers can be used as “biological filters” to identify genes that are important to cancer development and prioritise potential therapeutic targets. The example of MELK in prostate cancer.
Synopsis
Genetically engineered mouse models (GEMM) of human cancers can be used as “biological filters” to identify genes that are important to cancer development and prioritise potential therapeutic targets. The example of MELK in prostate cancer.
Comparisons of high‐throughput sequencing data from two GEMM of prostate cancer with human prostate cancer gene expression data revealed that human and murine tumours share common gene expression alterations.
Integration of human and murine gene expression data was used to identify potential therapeutic targets in prostate cancer, including the protein kinase MELK.
MELK is overexpressed in prostate cancer and associated with poor prognosis.
Silencing of MELK or treatment with an inhibitor targeting MELK resulted in induction of apoptosis in prostate cancer cells in vitro and in vivo.
EMBO Mol Med (2018) 10: e8274
- Received July 15, 2017.
- Revision received January 1, 2018.
- Accepted January 8, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1
- James W Peacock1,2,
- Ario Takeuchi1,3,
- Norihiro Hayashi1,4,
- Liangliang Liu1,
- Kevin J Tam1,2,
- Nader Al Nakouzi1,
- Nastaran Khazamipour1,
- Tabitha Tombe1,
- Takashi Dejima1,3,
- Kevin CK Lee1,
- Masaki Shiota1,3,
- Daksh Thaper1,2,
- Wilson CW Lee1,
- Daniel HF Hui1,
- Hidetoshi Kuruma1,
- Larissa Ivanova1,
- Parvin Yenki1,2,
- Ivy ZF Jiao1,
- Shahram Khosravi1,
- Alice L‐F Mui5,
- Ladan Fazli1,
- Amina Zoubeidi1,2,
- Mads Daugaard1,2,
- Martin E Gleave (m.gleave{at}ubc.ca)*,1,2 and
- Christopher J Ong (chris.ong{at}ubc.ca) (Chriso{at}mail.ubc.ca)*,1,2
- 1Vancouver Prostate Centre, Vancouver, BC, Canada
- 2Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- 3Department of Urology, Graduate School of Medical Sciences Kyushi University, Fukuoka, Japan
- 4Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
- 5Department of Surgery, University of British Columbia, Vancouver, BC, Canada
- ↵*
Corresponding author. Tel: +1 6046 752568; E‐mail: m.gleave{at}ubc.ca
Corresponding author. Tel: +1 6048 754111 ext. 63120; E‐mail: chris.ong{at}ubc.ca or Chriso{at}mail.ubc.ca
SEMA3C is a secreted autocrine factor that drives cancer growth and treatment resistance by transactivating multiple receptor tyrosine kinases via Plexin B1 in a cognate ligand‐independent manner. Antagonizing SEMA3C signaling inhibits prostate cancer growth in vitro and in vivo.
Synopsis
SEMA3C is a secreted autocrine factor that drives cancer growth and treatment resistance by transactivating multiple receptor tyrosine kinases via Plexin B1 in a cognate ligand‐independent manner. Antagonizing SEMA3C signaling inhibits prostate cancer growth in vitro and in vivo.
SEMA3C drives EGFR, ErbB2, and MET signaling cascades.
Plexin B1 (PLXNB1) is a receptor for SEMA3C.
Autocrine SEMA3C promotes prostate cancer growth and treatment resistance.
A recombinant PLEXIN B1 decoy protein attenuates SEMA3C signaling and prostate cancer growth.
EMBO Mol Med (2018) 10: 219–238
- Received February 14, 2017.
- Revision received November 22, 2017.
- Accepted December 1, 2017.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- CDK6 protects epithelial ovarian cancer from platinum‐induced death via FOXO3 regulation
- Alessandra Dall'Acqua1,
- Maura Sonego1,
- Ilenia Pellizzari1,
- Ilenia Pellarin1,
- Vincenzo Canzonieri2,
- Sara D'Andrea1,
- Sara Benevol1,
- Roberto Sorio3,
- Giorgio Giorda4,
- Daniela Califano5,
- Marina Bagnoli6,
- Loredana Militello3,
- Delia Mezzanzanica6,
- Gennaro Chiappetta5,
- Joshua Armenia1,
- Barbara Belletti1,
- Monica Schiappacassi (mschiappacassi{at}cro.it)*,1 and
- Gustavo Baldassarre (gbaldassarre{at}cro.it)*,1
- 1Division of Molecular Oncology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 2Division of Pathology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 3Division of Medical Oncology C, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 4Division of Gynecology‐Oncology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 5Genomica Funzionale, Istituto Nazionale Tumori ‐IRCCS‐ Fondazione G Pascale, Naples, Italy
- 6Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Milan, Italy
- ↵*
Corresponding author. Tel: +39 0434 659 759/661; Fax: +39 0434 659 428; E‐mail: mschiappacassi{at}cro.it
Corresponding author. Tel: +39 0434 659 759/661; Fax: +39 0434 659 428; E‐mail: gbaldassarre{at}cro.it
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
Synopsis
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
CDK6 in complex with cyclin D3 participates in the control of DNA damage response.
CDK6 binds and phosphorylates FOXO3 on serine 325 to control ATR expression.
High CDK6 expression predicts poor survival of EOC patients.
A combination of platinum‐based chemotherapy with pharmacological CDK6 inhibition might be a new therapeutic option for EOC patients.
EMBO Mol Med (2017) 9: 1415–1433
- Received August 30, 2016.
- Revision received July 10, 2017.
- Accepted July 11, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Going viral? Linking the etiology of human prostate cancer to the PCA3 long noncoding RNA and oncogenic viruses
- Andre A Teixeira1,2,3,†,
- Serena Marchiò1,2,4,5,†,
- Emmanuel Dias‐Neto6,7,
- Diana N Nunes6,
- Israel T da Silva8,
- Bryce Chackerian9,
- Marc Barry1,10,
- Richard C Lauer1,11,
- Ricardo J Giordano3,
- Richard L Sidman12,
- Cosette M Wheeler1,11,
- Webster K Cavenee13,
- Renata Pasqualini1,2,‡ and
- Wadih Arap1,11,‡
- 1University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA
- 2Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
- 3Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil
- 4Department of Oncology, University of Torino School of Medicine, Torino, TO, Italy
- 5Candiolo Cancer Institute‐Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, TO, Italy
- 6Laboratory of Medical Genomics, A.C.Camargo Cancer Center, São Paulo, Brazil
- 7Laboratory of Neurosciences, Institute of Psychiatry, University of São Paulo, São Paulo, Brazil
- 8Laboratory of Computational Biology, A.C.Camargo Cancer Center, São Paulo, Brazil
- 9Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, USA
- 10Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
- 11Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
- 12Department of Neurology, Harvard Medical School, Boston, MA, USA
- 13Ludwig Institute for Cancer Research, University of California‐San Diego, La Jolla, CA, USA
The hypothesis is discussed that prostate cancer marker lncRNA PCA3 was introduced into the human genome by an oncogenic virus, and that viral infection‐related mechanisms might underlie its overexpression and prostate cancer initiation and/or progression.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
- Zine‐Eddine Kherraf1,†,
- Marie Christou‐Kent1,†,
- Thomas Karaouzene1,
- Amir Amiri‐Yekta1,2,3,
- Guillaume Martinez1,
- Alexandra S Vargas1,
- Emeline Lambert1,
- Christelle Borel4,
- Béatrice Dorphin5,
- Isabelle Aknin‐Seifer6,
- Michael J Mitchell7,
- Catherine Metzler‐Guillemain7,
- Jessica Escoffier1,
- Serge Nef4,
- Mariane Grepillat1,
- Nicolas Thierry‐Mieg8,
- Véronique Satre1,9,
- Marc Bailly10,11,
- Florence Boitrelle10,11,
- Karin Pernet‐Gallay12,
- Sylviane Hennebicq1,13,
- Julien Fauré2,12,
- Serge P Bottari1,14,
- Charles Coutton1,9,
- Pierre F Ray (pray{at}chu-grenoble.fr)*,1,2,‡ and
- Christophe Arnoult1,‡
- 1Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- 2CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, France
- 3Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 4, Switzerland
- 5Laboratoire d'Aide Médicale à la Procréation, Centre AMP 74, Contamine‐sur‐Arve, France
- 6Laboratoire de Biologie de la Reproduction, Hôpital Nord, Saint Etienne, France
- 7Aix Marseille Univ INSERM GMGF, Marseille, France
- 8Univ. Grenoble Alpes / CNRS, TIMC‐IMAG, Grenoble, France
- 9CHU de Grenoble, UF de Génétique Chromosomique, Grenoble, France
- 10Department of Reproductive Biology and Gynaecology, Poissy General Hospital, Poissy, France
- 11EA 7404 GIG, Université de Versailles Saint Quentin Montigny le Bretonneux, France
- 12Grenoble Neuroscience Institute, INSERM 1216, Grenoble, France
- 13CHU de Grenoble, UF de Biologie de la procréation, Grenoble, France
- 14CHU de Grenoble, UF de Radioanalyses, Grenoble, France
- ↵*Corresponding author. Tel: +33 4 76 76 55 73; E‐mail: pray{at}chu-grenoble.fr
SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men.
Synopsis
SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men.
In round spermatids, SPINK2 is necessary to inactivate the acrosin during its transit through the endoplasmic reticulum and the Golgi apparatus.
In the absence of SPINK2, acrosin can auto‐activate, disorganize the Golgi apparatus, prevent the production of the acrosome and induce a block at the round spermatid stage.
A reduced amount of SPINK2 in heterozygotes is also deleterious, inducing a milder phenotype of oligozoospermia and/or teratozoospermia without a systematic infertility.
EMBO Mol Med (2017) 9: 1132–1149
- Received December 13, 2016.
- Revision received April 14, 2017.
- Accepted April 26, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models
- Kyle G Potts1,2,3,
- Chad R Irwin2,3,4,
- Nicole A Favis2,3,4,
- Desmond B Pink1,3,
- Krista M Vincent1,3,5,
- John D Lewis1,3,
- Ronald B Moore1,3,6,
- Mary M Hitt1,2,3,† and
- David H Evans (devans{at}ualberta.ca)*,2,3,4,†
- 1Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 2Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 3Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 4Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 5Department of Anatomy & Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- 6Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- ↵*Corresponding author. Tel: +1 780 492‐7997; E‐mail: devans{at}ualberta.ca
↵† These authors contributed equally to this work
Vaccinia virus (VACV) mutated to render it incapable of synthesizing deoxynucleoside triphosphates (dNTPs) is a safe, highly selective, and potentially superior oncolytic agent in animal models for bladder cancer.
Synopsis
Vaccinia virus (VACV) mutated to render it incapable of synthesizing deoxynucleoside triphosphates (dNTPs) is a safe, highly selective, and potentially superior oncolytic agent in animal models for bladder cancer.
F4L‐deleted VACVs are highly attenuated in normal tissues and selectively replicate in, and kill bladder cancer cells that express elevated RRM2 levels.
F4L‐deleted VACVs replicate selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity.
Rats cured of AY‐27 tumors by VACV treatment developed long‐lasting anti‐tumor immunity.
F4L‐deleted VACVs replicate in primary human bladder cancer explants and BCG‐resistant cell lines.
EMBO Mol Med (2017) 9: 638–654
- Received November 4, 2016.
- Revision received February 10, 2017.
- Accepted February 15, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Ethics of stem cell‐derived gametes made in a dish: fertility for everyone?
A timely and thoughtful discussion of the ethical challenges and societal impacts presented by the recent reports demonstrating the successful in vitro generation of functional gametes from somatic and pluripotent stem cells.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Peroxisome proliferator‐activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
- Oren Pleniceanu1,2,3,4,
- Racheli Shukrun1,2,4,
- Dorit Omer1,2,
- Einav Vax1,2,4,
- Itamar Kanter5,
- Klaudyna Dziedzic1,2,4,
- Naomi Pode‐Shakked1,2,4,†,
- Michal Mark‐Daniei1,2,
- Sara Pri‐Chen1,2,
- Yehudit Gnatek1,2,
- Hadas Alfandary4,6,
- Nira Varda‐Bloom3,
- Dekel D Bar‐Lev1,2,
- Naomi Bollag7,
- Rachel Shtainfeld7,
- Leah Armon7,
- Achia Urbach7,
- Tomer Kalisky5,
- Arnon Nagler3,4,†,
- Orit Harari‐Steinberg1,2,
- Jack L Arbiser8,9 and
- Benjamin Dekel (benjamin.dekel{at}gmail.com) (binyamin.dekel{at}sheba.health.gov.il)*,1,2,4
- 1Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- 2Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- 3Division of Hematology and Cord Blood Bank, Sheba Medical Center, Ramat Gan, Israel
- 4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- 5Faculty of Engineering, Institute of Nanotechnology, Bar‐Ilan University, Ramat Gan, Israel
- 6Institute of Nephrology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- 7The Mina and Everard Goodman Faculty of Life Sciences, Bar‐Ilan University, Ramat Gan, Israel
- 8Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
- 9Winship Cancer Institute, Atlanta Veterans Administration Hospital, Atlanta, GA, USA
- ↵*Corresponding author. Tel: +972 3 5302445; Fax: +972 3 5303637; E‐mail: benjamin.dekel{at}gmail.com or binyamin.dekel{at}sheba.health.gov.il
Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.
Synopsis
Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.
An AML xenograft (Xn) model, exhibiting the classic histology, immunophenotype, and gene expression pattern of human AML, was established by injection of human AML cells in mice.
AML Xn propagation in vivo is accompanied by robust activation of the PPARG pathway, and human AML tumors strongly express PPARG.
PPARG is expressed across all tumor compartments, indicating that rather than accompanying adipocytic differentiation, PPARG activation drives AML growth, and with the presence of fat in the tumor being its by‐product.
PPARG antagonism, via small molecules and shRNA, results in strong growth inhibition of AML, as well as abrogation of tumor initiation in mice.
Human AML cells exhibit striking similarity to human MSCs, in terms of gene expression, surface marker expression, and potential.
EMBO Mol Med (2017) 9: 508–530
- Received November 29, 2015.
- Revision received January 19, 2017.
- Accepted January 26, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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