ALBERT

Description: Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arpaia, Nicholas -- Campbell, Clarissa -- Fan, Xiying -- Dikiy, Stanislav -- van der Veeken, Joris -- deRoos, Paul -- Liu, Hui -- Cross, Justin R -- Pfeffer, Klaus -- Coffer, Paul J -- Rudensky, Alexander Y -- P30 CA008748/CA/NCI NIH HHS/ -- R37 AI034206/AI/NIAID NIH HHS/ -- R37AI034206/AI/NIAID NIH HHS/ -- T32 AI007621/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32A1007621/PHS HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):451-5. doi: 10.1038/nature12726. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany. ; 1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226773" target="_blank"〉PubMed〈/a〉

Description: In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes. Here we translate this 'albumin hitchhiking' approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069155/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069155/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Haipeng -- Moynihan, Kelly D -- Zheng, Yiran -- Szeto, Gregory L -- Li, Adrienne V -- Huang, Bonnie -- Van Egeren, Debra S -- Park, Clara -- Irvine, Darrell J -- AI091693/AI/NIAID NIH HHS/ -- AI095109/AI/NIAID NIH HHS/ -- AI104715/AI/NIAID NIH HHS/ -- F32 CA180586/CA/NCI NIH HHS/ -- P01 AI104715/AI/NIAID NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 AI095109/AI/NIAID NIH HHS/ -- U19 AI091693/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 27;507(7493):519-22. doi: 10.1038/nature12978. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02139, USA [5] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531764" target="_blank"〉PubMed〈/a〉

Description: Monoclonal antibodies have become important therapeutic agents against certain cancers. Many tumor-specific antigens are mutant proteins that are predominantly intracellular and thus not readily accessible to monoclonal antibodies. We found that a wild-type transmembrane protein could be transformed into a tumor-specific antigen. A somatic mutation in the chaperone gene Cosmc abolished function of a glycosyltransferase, disrupting O-glycan Core 1 synthesis and creating a tumor-specific glycopeptidic neo-epitope consisting of a monosaccharide and a specific wild-type protein sequence. This epitope induced a high-affinity, highly specific, syngeneic monoclonal antibody with antitumor activity. Such tumor-specific glycopeptidic neo-epitopes represent potential targets for monoclonal antibody therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schietinger, Andrea -- Philip, Mary -- Yoshida, Barbara A -- Azadi, Parastoo -- Liu, Hui -- Meredith, Stephen C -- Schreiber, Hans -- HD 07009/HD/NICHD NIH HHS/ -- P01-CA97296/CA/NCI NIH HHS/ -- P41RR018502-01/RR/NCRR NIH HHS/ -- R01-CA22677/CA/NCI NIH HHS/ -- R01-CA37516/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2006 Oct 13;314(5797):304-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Committee on Immunology, Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA. aschieti@uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17038624" target="_blank"〉PubMed〈/a〉

Description: The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Hongjun -- Fergusson, Maria M -- Castilho, Rogerio M -- Liu, Jie -- Cao, Liu -- Chen, Jichun -- Malide, Daniela -- Rovira, Ilsa I -- Schimel, Daniel -- Kuo, Calvin J -- Gutkind, J Silvio -- Hwang, Paul M -- Finkel, Toren -- 1 R01 DK069989-01/DK/NIDDK NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2007 Aug 10;317(5839):803-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17690294" target="_blank"〉PubMed〈/a〉

Description: Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1alpha and nuclear lamina-heterochromatin anchoring protein LAP2beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Weiqi -- Li, Jingyi -- Suzuki, Keiichiro -- Qu, Jing -- Wang, Ping -- Zhou, Junzhi -- Liu, Xiaomeng -- Ren, Ruotong -- Xu, Xiuling -- Ocampo, Alejandro -- Yuan, Tingting -- Yang, Jiping -- Li, Ying -- Shi, Liang -- Guan, Dee -- Pan, Huize -- Duan, Shunlei -- Ding, Zhichao -- Li, Mo -- Yi, Fei -- Bai, Ruijun -- Wang, Yayu -- Chen, Chang -- Yang, Fuquan -- Li, Xiaoyu -- Wang, Zimei -- Aizawa, Emi -- Goebl, April -- Soligalla, Rupa Devi -- Reddy, Pradeep -- Esteban, Concepcion Rodriguez -- Tang, Fuchou -- Liu, Guang-Hui -- Belmonte, Juan Carlos Izpisua -- F32 AG047770/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. Epub 2015 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ; Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ; State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. ; Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; College of Life Sciences, Peking University, Beijing 100871, China. ; The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Universidad Catolica San Antonio de Murcia, Campus de los Jeronimos s/n, 30107 Guadalupe, Murcia, Spain. ; Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu. ; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Beijing Institute for Brain Disorders, Beijing 100069, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25931448" target="_blank"〉PubMed〈/a〉

Description: G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a approximately 20 degrees rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Yanyong -- Zhou, X Edward -- Gao, Xiang -- He, Yuanzheng -- Liu, Wei -- Ishchenko, Andrii -- Barty, Anton -- White, Thomas A -- Yefanov, Oleksandr -- Han, Gye Won -- Xu, Qingping -- de Waal, Parker W -- Ke, Jiyuan -- Tan, M H Eileen -- Zhang, Chenghai -- Moeller, Arne -- West, Graham M -- Pascal, Bruce D -- Van Eps, Ned -- Caro, Lydia N -- Vishnivetskiy, Sergey A -- Lee, Regina J -- Suino-Powell, Kelly M -- Gu, Xin -- Pal, Kuntal -- Ma, Jinming -- Zhi, Xiaoyong -- Boutet, Sebastien -- Williams, Garth J -- Messerschmidt, Marc -- Gati, Cornelius -- Zatsepin, Nadia A -- Wang, Dingjie -- James, Daniel -- Basu, Shibom -- Roy-Chowdhury, Shatabdi -- Conrad, Chelsie E -- Coe, Jesse -- Liu, Haiguang -- Lisova, Stella -- Kupitz, Christopher -- Grotjohann, Ingo -- Fromme, Raimund -- Jiang, Yi -- Tan, Minjia -- Yang, Huaiyu -- Li, Jun -- Wang, Meitian -- Zheng, Zhong -- Li, Dianfan -- Howe, Nicole -- Zhao, Yingming -- Standfuss, Jorg -- Diederichs, Kay -- Dong, Yuhui -- Potter, Clinton S -- Carragher, Bridget -- Caffrey, Martin -- Jiang, Hualiang -- Chapman, Henry N -- Spence, John C H -- Fromme, Petra -- Weierstall, Uwe -- Ernst, Oliver P -- Katritch, Vsevolod -- Gurevich, Vsevolod V -- Griffin, Patrick R -- Hubbell, Wayne L -- Stevens, Raymond C -- Cherezov, Vadim -- Melcher, Karsten -- Xu, H Eric -- DK071662/DK/NIDDK NIH HHS/ -- EY005216/EY/NEI NIH HHS/ -- EY011500/EY/NEI NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM077561/GM/NIGMS NIH HHS/ -- GM095583/GM/NIGMS NIH HHS/ -- GM097463/GM/NIGMS NIH HHS/ -- GM102545/GM/NIGMS NIH HHS/ -- GM103310/GM/NIGMS NIH HHS/ -- GM104212/GM/NIGMS NIH HHS/ -- GM108635/GM/NIGMS NIH HHS/ -- P30EY000331/EY/NEI NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 EY011500/EY/NEI NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM109955/GM/NIGMS NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA. ; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany. ; Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, New York 10027, USA. ; Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA [2] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, Arizona State University, Tempe, Arizona 85287, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Beijing Computational Science Research Center, Haidian District, Beijing 10084, China. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA. ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. ; 1] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA [2] Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA. ; Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biology, Universitat Konstanz, 78457 Konstanz, Germany. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; 1] Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany [2] Centre for Ultrafast Imaging, 22761 Hamburg, Germany. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [2] Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200343" target="_blank"〉PubMed〈/a〉

Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Osswald, Matthias -- Jung, Erik -- Sahm, Felix -- Solecki, Gergely -- Venkataramani, Varun -- Blaes, Jonas -- Weil, Sophie -- Horstmann, Heinz -- Wiestler, Benedikt -- Syed, Mustafa -- Huang, Lulu -- Ratliff, Miriam -- Karimian Jazi, Kianush -- Kurz, Felix T -- Schmenger, Torsten -- Lemke, Dieter -- Gommel, Miriam -- Pauli, Martin -- Liao, Yunxiang -- Haring, Peter -- Pusch, Stefan -- Herl, Verena -- Steinhauser, Christian -- Krunic, Damir -- Jarahian, Mostafa -- Miletic, Hrvoje -- Berghoff, Anna S -- Griesbeck, Oliver -- Kalamakis, Georgios -- Garaschuk, Olga -- Preusser, Matthias -- Weiss, Samuel -- Liu, Haikun -- Heiland, Sabine -- Platten, Michael -- Huber, Peter E -- Kuner, Thomas -- von Deimling, Andreas -- Wick, Wolfgang -- Winkler, Frank -- England -- Nature. 2015 Dec 3;528(7580):93-8. doi: 10.1038/nature16071. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany. ; Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany. ; Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universitat Munchen, 81675 Munich, Germany. ; Neurosurgery Clinic, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Department of Neuroradiology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Department of Neurophysiology, Institute of Physiology, University of Wurzburg, 97070 Wurzburg, Germany. ; Department of Medical Physics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. ; Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. ; Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria. ; Tools For Bio-Imaging, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany. ; Institute of Physiology II, Eberhard Karls University of Tubingen, 72074 Tubingen, Germany. ; Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria. ; Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada. ; Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada. ; Clark Smith Brain Tumor Research Centre, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada. ; Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; CCU Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany. ; Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536111" target="_blank"〉PubMed〈/a〉