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  • 1
    Abstract: The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy.
    Type of Publication: Journal article published
    PubMed ID: 25749382
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  • 2
    Keywords: MODEL ; CELL-CYCLE ; REVEALS ; DNA-DAMAGE RESPONSE
    Abstract: KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.
    Type of Publication: Journal article published
    PubMed ID: 26140595
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  • 3
    Keywords: carcinoma ; IN-VIVO ; PATHWAY ; GENES ; MUTATIONS ; MOUSE MODEL ; C-KIT ; CYCLE ARREST ; NEUROENDOCRINE TUMORS ; NOTCH
    Abstract: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Deltaex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
    Type of Publication: Journal article published
    PubMed ID: 26168399
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  • 4
    Abstract: The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression. RNA-seq and comprehensive pathway analysis revealed, that genes related to a recently described non-canonical integrin beta3 pathway, were significantly downregulated by LSD1 silencing. Hence, invasion and self-renewal capabilities were strongly decreased. Notably, this novel defined LSD1/integrin beta3 axis, was also detected in human lung adenocarcinoma specimens. Furthermore, the linkage of LSD1 to an altered expression pattern of lung-lineage specific transcription factors and genes, which are involved in alveolar epithelial differentiation, was demonstrated. Thus, our findings point to a LSD1-integrin beta3 axis, conferring attributes of invasiveness and tumor progression to lung adenocarcinoma.
    Type of Publication: Journal article published
    PubMed ID: 28860622
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  • 5
    Publication Date: 2015-07-15
    Description: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Deltaex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Julie -- Lim, Jing Shan -- Jang, Se Jin -- Cun, Yupeng -- Ozretic, Luka -- Kong, Gu -- Leenders, Frauke -- Lu, Xin -- Fernandez-Cuesta, Lynnette -- Bosco, Graziella -- Muller, Christian -- Dahmen, Ilona -- Jahchan, Nadine S -- Park, Kwon-Sik -- Yang, Dian -- Karnezis, Anthony N -- Vaka, Dedeepya -- Torres, Angela -- Wang, Maia Segura -- Korbel, Jan O -- Menon, Roopika -- Chun, Sung-Min -- Kim, Deokhoon -- Wilkerson, Matt -- Hayes, Neil -- Engelmann, David -- Putzer, Brigitte -- Bos, Marc -- Michels, Sebastian -- Vlasic, Ignacija -- Seidel, Danila -- Pinther, Berit -- Schaub, Philipp -- Becker, Christian -- Altmuller, Janine -- Yokota, Jun -- Kohno, Takashi -- Iwakawa, Reika -- Tsuta, Koji -- Noguchi, Masayuki -- Muley, Thomas -- Hoffmann, Hans -- Schnabel, Philipp A -- Petersen, Iver -- Chen, Yuan -- Soltermann, Alex -- Tischler, Verena -- Choi, Chang-min -- Kim, Yong-Hee -- Massion, Pierre P -- Zou, Yong -- Jovanovic, Dragana -- Kontic, Milica -- Wright, Gavin M -- Russell, Prudence A -- Solomon, Benjamin -- Koch, Ina -- Lindner, Michael -- Muscarella, Lucia A -- la Torre, Annamaria -- Field, John K -- Jakopovic, Marko -- Knezevic, Jelena -- Castanos-Velez, Esmeralda -- Roz, Luca -- Pastorino, Ugo -- Brustugun, Odd-Terje -- Lund-Iversen, Marius -- Thunnissen, Erik -- Kohler, Jens -- Schuler, Martin -- Botling, Johan -- Sandelin, Martin -- Sanchez-Cespedes, Montserrat -- Salvesen, Helga B -- Achter, Viktor -- Lang, Ulrich -- Bogus, Magdalena -- Schneider, Peter M -- Zander, Thomas -- Ansen, Sascha -- Hallek, Michael -- Wolf, Jurgen -- Vingron, Martin -- Yatabe, Yasushi -- Travis, William D -- Nurnberg, Peter -- Reinhardt, Christian -- Perner, Sven -- Heukamp, Lukas -- Buttner, Reinhard -- Haas, Stefan A -- Brambilla, Elisabeth -- Peifer, Martin -- Sage, Julien -- Thomas, Roman K -- 5R01CA114102-08/CA/NCI NIH HHS/ -- England -- Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA. ; Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea. ; Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada. ; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany. ; Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany. ; Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany. ; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany. ; 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain. ; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. ; 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. ; Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. ; 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. ; Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany. ; Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA. ; University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia. ; Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Pathology, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Asklepios Biobank fur Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken Munchen-Gauting 82131, Germany. ; Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy. ; Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre, 200 London Road, L69 3GA Liverpool, UK. ; University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, 10000 Zagreb, Croatia. ; Laboratory for Translational Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia. ; Charite Comprehensive Cancer Center, Charite Campus Mitte, 10115 Berlin, Germany. ; Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS - Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. ; Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy. ; 1] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway. [2] Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. ; 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden. ; Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain. ; 1] Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, N-5058 Bergen, Norway. [2] Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; 1] Computing Center, University of Cologne, 50931 Cologne, Germany. [2] Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany. ; Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50937 Cologne, Germany. ; 1] Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 464-8681 Nagoya, Japan. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. [3] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26168399" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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