- Research ArticleDual reporter genetic mouse models of pancreatic cancer identify an epithelial‐to‐mesenchymal transition‐independent metastasis program
- Yang Chen1,
- Valerie S LeBleu1,
- Julienne L Carstens1,
- Hikaru Sugimoto1,
- Xiaofeng Zheng1,
- Shruti Malasi1,
- Dieter Saur2,3 and
- Raghu Kalluri (rkalluri{at}mdanderson.org)*,1
- 1Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 2Department of Medicine II Klinikum rechts der Isar, Technische Universität München, München, Germany
- 3German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- ↵*Corresponding author. Tel: +1 713 994 5310; E‐mail: rkalluri{at}mdanderson.org
Epithelial‐to‐mesenchymal transition (EMT) is considered essential for pancreatic cancer metastasis. This study identifies non‐EMT‐mediated metastasis by lineage tracing partial EMT via a dual‐recombinase system in mice with fluorescence‐switching reporters and mesenchymal fate mapping transgenes.
Synopsis
Epithelial‐to‐mesenchymal transition (EMT) is considered essential for pancreatic cancer metastasis. This study identifies non‐EMT‐mediated metastasis by lineage tracing partial EMT via a dual‐recombinase system in mice with fluorescence‐switching reporters and mesenchymal fate mapping transgenes.
Partial EMT programs were observed in 2–3% cancer cells of the primary PDAC tumors, as captured by the lineage‐tracing system.
Established lung and liver metastases were composed of cancer cells without evidence for partial EMT program, as determined by the acquisition of mesenchymal markers such as αSMA, FSP1 or vimentin.
Metastatic cancer cells exhibiting a partial EMT program were observed only as disseminated single cancer cells or micrometastases (3–5 cells), but did not grow to become large secondary tumors.
EMBO Mol Med (2018) e9085
- Received March 7, 2018.
- Revision received July 12, 2018.
- Accepted July 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.
- Research ArticleCEP55 is a determinant of cell fate during perturbed mitosis in breast cancer
- Murugan Kalimutho (murugan.kalimutho{at}qimrberghofer.edu.au)*,1,2,†,
- Debottam Sinha1,2,†,
- Jessie Jeffery1,
- Katia Nones1,3,
- Sriganesh Srihari4,
- Winnie C Fernando1,
- Pascal HG Duijf5,
- Claire Vennin6,7,
- Prahlad Raninga1,
- Devathri Nanayakkara1,
- Deepak Mittal1,
- Jodi M Saunus1,8,
- Sunil R Lakhani8,9,10,
- J Alejandro López1,2,
- Kevin J Spring11,12,13,
- Paul Timpson6,7,
- Brian Gabrielli5,14,
- Nicola Waddell1 and
- Kum Kum Khanna (kumkum.khanna{at}qimrberghofer.edu.au)*,1
- 1QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- 2School of Natural Sciences, Griffith University, Nathan, Qld, Australia
- 3Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia
- 4Computational Systems Biology Laboratory, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia
- 5University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
- 6Cancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia
- 7Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
- 8Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
- 9School of Medicine, The University of Queensland, Herston, Qld, Australia
- 10Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Qld, Australia
- 11Liverpool Clinical School, University of Western Sydney, Liverpool, NSW, Australia
- 12Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
- 13South Western Sydney Clinical School, University of New South Wales, Liverpool, NSW, Australia
- 14Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
- ↵*
Corresponding author. Tel: +61 38453772; E‐mail: murugan.kalimutho{at}qimrberghofer.edu.au
Corresponding author. Tel: +61 7 3362 0338; E‐mail: kumkum.khanna{at}qimrberghofer.edu.au
↵† These authors contributed equally to this work
By integrating analyses of multiple in vitro and in vivo breast cancer models, this study provides direct evidence for CEP55‐mediated protection of aneuploidy. Targeting MEK1/2‐PLK1 axis in CEP55‐MYC‐dependent basal‐like, triple‐negative breast cancers could be a novel treatment strategy.
Synopsis
By integrating analyses of multiple in vitro and in vivo breast cancer models, this study provides direct evidence for CEP55‐mediated protection of aneuploidy. Targeting MEK1/2‐PLK1 axis in CEP55‐MYC‐dependent basal‐like, triple‐negative breast cancers could be a novel treatment strategy.
CEP55 overexpression is associated with poor clinical outcomes in breast cancer.
CEP55 dictates cell fate during perturbed mitosis.
High levels of CEP55 are protective in aneuploid cells.
Loss of CEP55 primes premature CDK1/Cyclin B activation and apoptosis upon treatment with anti‐mitotic drugs.
Cep55 is a marker for rationale use of combined MEK1/2‐PLK1 inhibition in triple‐negative breast cancers.
EMBO Mol Med (2018) e8566
- Received October 9, 2017.
- Revision received July 15, 2018.
- Accepted July 18, 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.
- ReportComprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer
- Johanna Kondelin1,2,
- Kari Salokas3,4,
- Lilli Saarinen2,
- Kristian Ovaska2,
- Heli Rauanheimo1,2,
- Roosa‐Maria Plaketti1,2,
- Jiri Hamberg1,2,
- Xiaonan Liu3,4,
- Leena Yadav3,4,
- Alexandra E Gylfe1,2,
- Tatiana Cajuso1,2,
- Ulrika A Hänninen1,2,
- Kimmo Palin1,2,
- Heikki Ristolainen1,2,
- Riku Katainen1,2,
- Eevi Kaasinen1,2,
- Tomas Tanskanen1,2,
- Mervi Aavikko1,2,
- Minna Taipale5,
- Jussi Taipale1,2,6,7,
- Laura Renkonen‐Sinisalo8,
- Anna Lepistö8,
- Selja Koskensalo9,
- Jan Böhm10,
- Jukka‐Pekka Mecklin11,12,
- Halit Ongen13,14,15,
- Emmanouil T Dermitzakis13,14,15,
- Outi Kilpivaara1,2,
- Pia Vahteristo1,2,
- Mikko Turunen2,
- Sampsa Hautaniemi2,
- Sari Tuupanen1,2,
- Auli Karhu1,2,
- Niko Välimäki1,2,
- Markku Varjosalo3,4,
- Esa Pitkänen1,2 and
- Lauri A Aaltonen (lauri.aaltonen{at}helsinki.fi)*,1,2
- 1Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
- 2Genome‐Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
- 3Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- 4Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- 5Division of Functional Genomics, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, Stockholm, Sweden
- 6Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
- 7Science for Life Center, Huddinge, Sweden
- 8Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland
- 9The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Helsinki, Finland
- 10Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
- 11Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland
- 12Department Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
- 13Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- 14Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
- 15Swiss Institute of Bioinformatics, Geneva, Switzerland
- ↵*Corresponding author. Tel: +358 2941 25595; E‐mail: lauri.aaltonen{at}helsinki.fi
To date, only few genes with causative point mutations are known in microsatellite instability in colorectal cancers (MSI CRC), most having been flagged by missense mutation hot spots. This study identifies candidate cancer driving genes based on exome‐wide somatic mutation data from MSI CRC.
Synopsis
To date, only few genes with causative point mutations are known in microsatellite instability in colorectal cancers (MSI CRC), most having been flagged by missense mutation hot spots. This study identifies candidate cancer driving genes based on exome‐wide somatic mutation data from MSI CRC.
A ranked list of 57 candidate MSI CRC driver genes is defined.
SMARCB1 exhibited altered interactions with several proteins with enrichment of alterations for the pentose phosphate pathway, and increased colony formation in CRC cells.
STK38L exhibited altered interaction with several interaction partners, of which many have been previously linked to cancer.
Seven novel hot spot containing candidate oncogenes CORIN, KLHL6, PCDHB16, PLEKHG1, PROS1, SPP2, and TROAP are identified.
EMBO Mol Med (2018) e8552
- Received October 5, 2017.
- Revision received July 6, 2018.
- Accepted July 9, 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.
- Research ArticleComparative proteomics reveals a diagnostic signature for pulmonary head‐and‐neck cancer metastasis
- Hanibal Bohnenberger1,†,
- Lars Kaderali2,†,
- Philipp Ströbel1,
- Diego Yepes3,4,
- Uwe Plessmann5,
- Neekesh V Dharia6,7,8,
- Sha Yao1,
- Carina Heydt9,
- Sabine Merkelbach‐Bruse9,
- Alexander Emmert10,
- Jonatan Hoffmann1,
- Julius Bodemeyer1,
- Kirsten Reuter‐Jessen1,
- Anna‐Maria Lois1,
- Leif Hendrik Dröge11,
- Philipp Baumeister12,
- Christoph Walz13,
- Lorenz Biggemann14,
- Roland Walter3,
- Björn Häupl3,4,
- Federico Comoglio15,16,
- Kuan‐Ting Pan5,
- Sebastian Scheich3,
- Christof Lenz5,17,
- Stefan Küffer1,
- Felix Bremmer1,
- Julia Kitz1,
- Maren Sitte18,
- Tim Beißbarth18,
- Marc Hinterthaner10,
- Martin Sebastian3,
- Joachim Lotz14,19,
- Hans‐Ulrich Schildhaus1,
- Hendrik Wolff20,21,
- Bernhard C Danner10,
- Christian Brandts3,4,
- Reinhard Büttner9,
- Martin Canis12,
- Kimberly Stegmaier6,7,8,
- Hubert Serve3,4,
- Henning Urlaub5,14 and
- Thomas Oellerich (thomas.oellerich{at}kgu.de)*,3,4
- 1Institute of Pathology, University Medical Center, Göttingen, Germany
- 2Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany
- 3Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany
- 4German Cancer Research Center, German Cancer Consortium, Heidelberg, Germany
- 5Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
- 6Department of Pediatric Oncology, Dana‐Farber Cancer Institute, Boston, MA, USA
- 7Division of Pediatric Hematology/Oncology, Boston Childrens Hospital, Boston, MA, USA
- 8The Broad Institute, Cambridge, MA, USA
- 9Institute of Pathology, University Hospital Cologne, University of Cologne, Köln, Germany
- 10Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen, Germany
- 11Department of Radiooncology, University Medical Center, Göttingen, Germany
- 12Department of Otorhinolaryngology, University Hospital Munich, Ludwig‐Maximilian‐University München, München, Germany
- 13Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
- 14Institute for Diagnostic and Interventional Radiology, University Medical Center, Göttingen, Germany
- 15Department of Haematology, University of Cambridge, Cambridge, UK
- 16Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK
- 17Bioanalytics, University Medical Center, Göttingen, Germany
- 18Institute of Medical Statistics, University Medical Center, Göttingen, Germany
- 19German Cardiovascular Research Center, Deutsches Zentrum für Herz‐Kreislaufforschung (DZHK), Partnersite Göttingen, Germany
- 20University Medical Center, Göttingen, Germany
- 21Department of Radiooncology, University Medical Center, Regensburg, Germany
- ↵*Corresponding author. Tel: +496963016148; E‐mail: thomas.oellerich{at}kgu.de
↵† These authors contributed equally to this work as first authors
Differentiation between head‐and‐neck cancer metastasis and primary lung cancer is clinically important for therapy selection. A novel diagnostic proteomic signature allows differentiation between these tumour types, and a proteomic resource for squamous cell tumours is here provided.
Synopsis
Differentiation between head‐and‐neck cancer metastasis and primary lung cancer is clinically important for therapy selection. A novel diagnostic proteomic signature allows differentiation between these tumour types, and a proteomic resource for squamous cell tumours is here provided.
The protein expression profiles of 63 squamous cell lung and 49 head‐and‐neck tumours were analysed by quantitative mass spectrometry yielding a proteomic resource covering 6,214 quantified proteins.
518 proteins were found to be differentially expressed between squamous cell lung and head‐and‐neck cancers which are known to share genomic and morphological features.
A diagnostic proteomic signature for differentiation between primary squamous cell lung cancers and head‐and‐neck cancer metastases was identified by quantitative mass‐spectrometry‐based proteomics and validated in independent patient cohorts.
EMBO Mol Med (2018) e8428
- Received September 19, 2017.
- Revision received July 9, 2018.
- Accepted July 10, 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.
- Research ArticleEnriched environment enhances β‐adrenergic signaling to prevent microglia inflammation by amyloid‐β
- 1Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- 2Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
- ↵*Corresponding author. Tel: +1 617 525 5200; E‐mail: dselkoe{at}bwh.harvard.edu
Environmental enrichment (EE) may provide protection against features of Alzheimer's disease but its impact on innate immunity lacks mechanistic understanding. EE in mice is shown to protect microglia from inflammation by amyloid beta‐protein oligomers via enhanced beta‐adrenergic signaling in vivo.
Synopsis
Environmental enrichment (EE) may provide protection against features of Alzheimer's disease but its impact on innate immunity lacks mechanistic understanding. EE in mice is shown to protect microglia from inflammation by amyloid beta‐protein oligomers via enhanced beta‐adrenergic signaling in vivo.
Pharmacological agonism and antagonism of beta‐adrenergic signaling respectively mimics or blocks the benefits of EE against Abeta in wild‐type mice.
Mice lacking beta‐adrenergic receptors fail to experience anti‐Abeta microglial protection from EE.
Microglial beta‐adrenergic signaling in the dentate gyrus is disrupted by Abeta and rescued by EE.
The ability of beta‐adrenergic signaling to neutralize oAbeta‐induced microglia inflammation is partially cAMP‐dependent.
EMBO Mol Med (2018) e8931
- Received January 29, 2018.
- Revision received July 12, 2018.
- Accepted July 16, 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.
- OpinionShould the 14‐day rule for embryo research become the 28‐day rule?
The “14‐day rule”—broadly construed—is used in science policy and regulation to limit research on human embryos to a maximum period of 14 days after their creation or to the equivalent stage of development that is normally attributed to a 14‐day‐old embryo (Hyun et al, 2016; Nuffield Council on Bioethics, 2017). For several decades, the 14‐day rule has been a shining example of how science policy and regulation can be developed with interdisciplinary consensus and applied across a number of countries to help fulfil an ethical and practical purpose: to facilitate efficient and ethical embryo research. However, advances in embryology and biomedical research have led to suggestions that the 14‐day rule is no longer adequate (Deglincerti et al, 2016; Shahbazi et al, 2016; Hurlbut et al, 2017). Therefore, should the 14‐day rule be extended and, if so, where should we draw a new line for permissible embryo research? Here, we provide scientific, regulatory and ethical arguments that the 14‐day rule should be extended to 28 days (or the developmental equivalent stage of a 28‐day‐old embryo).
The “14‐day rule” is used in science policy and regulation to limit research on human embryos to a maximum period of 14 days after their creation. In this modern era of technological advancement and greater needs for biomedical research, isn't the rule too limited? By Annelien Bredenoord & John Appleby.
EMBO Mol Med (2018) e9437
- © 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.
- Research ArticleEGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors
- Nevenka Dudvarski Stanković1,2,3,†,
- Frank Bicker1,2,3,†,
- Stefanie Keller1,2,3,†,
- David TW Jones3,4,5,6,
- Patrick N Harter2,3,7,
- Arne Kienzle1,8,
- Clarissa Gillmann9,
- Philipp Arnold10,
- Anna Golebiewska11,
- Olivier Keunen11,
- Alf Giese12,
- Andreas von Deimling3,4,13,
- Tobias Bäuerle9,
- Simone P Niclou11,14,
- Michel Mittelbronn11,15,16,17,
- Weilan Ye18,
- Stefan M Pfister3,4,5,6 and
- Mirko HH Schmidt (mirko.schmidt{at}unimedizin-mainz.de)*,1,2,3
- 1Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- 2German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Germany
- 3German Cancer Research Center (DKFZ), Heidelberg, Germany
- 4German Cancer Consortium (DKTK), Partner Site Heidelberg, Germany
- 5Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
- 6Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany
- 7Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany
- 8Laboratory of Adaptive and Regenerative Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- 9Institute of Radiology, University Medical Center Erlangen, Erlangen, Germany
- 10Anatomical Institute, Kiel University, Kiel, Germany
- 11NORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.), Luxembourg, Luxembourg
- 12Department of Neurosurgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- 13Department of Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- 14KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
- 15Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch‐sur‐Alzette, Luxembourg
- 16Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- 17Luxembourg Centre of Neuropathology (LCNP), Dudelange, Luxembourg
- 18Vascular Biology Program, Molecular Oncology Division, Genentech, San Francisco, CA, USA
- ↵*Corresponding author. Tel: +49 6131 17 8071; Fax: +49 6131 1747 8071; E‐mail: mirko.schmidt{at}unimedizin-mainz.de
↵† These authors contributed equally to this work
Glioblastoma are lethal brain tumors with currently no cure available. Combinatorial inhibition of the proangiogenic proteins EGFL7 and VEGF together with the chemotherapeutic agent temozolomide may serve as a novel treatment option for patients suffering from this futile disease.
Synopsis
Glioblastoma are lethal brain tumors with currently no cure available. Combinatorial inhibition of the proangiogenic proteins EGFL7 and VEGF together with the chemotherapeutic agent temozolomide may serve as a novel treatment option for patients suffering from this futile disease.
Application of EGFL7 and VEGF inhibitors alongside with the chemotherapeutic temozolomide may serve as a novel treatment option for lethal brain tumors.
EGFL7 acts as a pro‐angiogenic and pro‐tumorigenic factor in malignant glioma.
EGFL7 promotes blood vessel maturation rendering them less leaky in experimental glioma.
EGFL7 promotes angiogenesis by the modulation of intracellular trafficking of integrin α5β1.
EGFL7 acts independent of its parasitic miRNAs miR126/126*.
EMBO Mol Med (2018) e8420
- Received August 23, 2017.
- Revision received July 2, 2018.
- Accepted July 9, 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.
