Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.
| Title: | Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation. |
|---|---|
| Authors: | Javaheri T; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Kazemi Z; Medical University of Vienna, Vienna, Austria.; Center of Physiology and Pharmacology, Vienna, Austria.; Pencik J; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Medical University of Vienna, Vienna, Austria.; Clinical Institute of Pathology, Vienna, Austria.; Pham HT; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Kauer M; Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.; Noorizadeh R; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Sax B; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Nivarthi H; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Schlederer M; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Medical University of Vienna, Vienna, Austria.; Clinical Institute of Pathology, Vienna, Austria.; Maurer B; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Hofbauer M; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Aryee DN; Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.; Department of Pediatrics, Medical University of Vienna, Vienna, Austria.; Wiedner M; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Tomazou EM; Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.; Logan M; Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.; Hartmann C; Department of Bone and Skeletal Research, Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.; Tuckermann JP; Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.; Kenner L; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Medical University of Vienna, Vienna, Austria.; Clinical Institute of Pathology, Vienna, Austria.; University of Veterinary Medicine, Vienna, Austria.; Mikula M; Medical University of Vienna, Vienna, Austria.; Institute of Medical Genetics, Vienna, Austria.; Dolznig H; Medical University of Vienna, Vienna, Austria.; Institute of Medical Genetics, Vienna, Austria.; Üren A; Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, USA.; Richter GH; Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.; Grebien F; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Kovar H; Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.; Department of Pediatrics, Medical University of Vienna, Vienna, Austria.; Moriggl R; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Medical University of Vienna, Vienna, Austria. |
| Source: | Cell death & disease [Cell Death Dis] 2016 Oct 13; Vol. 7 (10), pp. e2419. Date of Electronic Publication: 2016 Oct 13. |
| Publication Type: | Journal Article; Retracted Publication |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : Nature Pub. Group |
| MeSH Terms: | Cell Cycle*; Cell Transformation, Neoplastic/*pathology ; Oncogene Proteins, Fusion/*metabolism ; Proto-Oncogene Protein c-fli-1/*metabolism ; RNA-Binding Protein EWS/*metabolism; Bone and Bones/pathology ; Cell Transformation, Neoplastic/metabolism ; Extremities/pathology ; Human Embryonic Stem Cells/metabolism ; Mesenchymal Stem Cells/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Animals ; Animals, Newborn ; Apoptosis ; Cell Cycle Checkpoints ; Cell Differentiation ; Cell Proliferation ; Cell Survival ; Gene Expression Profiling ; Gene Knockdown Techniques ; Humans ; Mice ; Osteogenesis ; Signal Transduction ; Transduction, Genetic |
| Abstract: | Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer. |
| Comments: | Erratum in: Cell Death Dis. 2018 Jul 23;9(8):800. doi: 10.1038/s41419-018-0773-9.. (PMID: 30038364); Retraction in: Cell Death Dis. 2019 Aug 13;10(8):605. doi: 10.1038/s41419-019-1853-1.. (PMID: 31406155) |
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| Grant Information: | 636855 International ERC_ European Research Council; MC_PC_13052 United Kingdom MRC_ Medical Research Council |
| Substance Nomenclature: | 0 (EWS-FLI fusion protein); 0 (Mcl1 protein, mouse); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Oncogene Proteins, Fusion); 0 (Proto-Oncogene Protein c-fli-1); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (RNA-Binding Protein EWS) |
| Entry Date(s): | Date Created: 20161014 Date Completed: 20170731 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5133963 |
| DOI: | 10.1038/cddis.2016.268 |
| PMID: | 27735950 |
| Database: | MEDLINE |
Journal Article; Retracted Publication