title: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.
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.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Javaheri
authors.affiliation: Medical University of Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Vienna, Austria.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kazemi
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.|Clinical Institute of Pathology, Vienna, Austria.
authors.forename: Jan
authors.initials: J
authors.lastname: Pencik
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Ha Tt
authors.initials: HT
authors.lastname: Pham
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kauer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Rahil
authors.initials: R
authors.lastname: Noorizadeh
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sax
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Harini
authors.initials: H
authors.lastname: Nivarthi
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.|Clinical Institute of Pathology, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Hofbauer
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Dave Nt
authors.initials: DN
authors.lastname: Aryee
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Marc
authors.initials: M
authors.lastname: Wiedner
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Tomazou
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Logan
authors.affiliation: Department of Bone and Skeletal Research, Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Medical University of Vienna, Vienna, Austria.|Institute of Medical Genetics, Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.affiliation: Medical University of Vienna, Vienna, Austria.|Institute of Medical Genetics, Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.affiliation: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, USA.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
authors.affiliation: Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Günther H
authors.initials: GH
authors.lastname: Richter
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001842:Bone and Bones / Q000473:pathology; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005121:Extremities / Q000473:pathology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010012:Osteogenesis; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: C106031:EWS-FLI fusion protein; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D019253:Proto-Oncogene Proteins c-bcl-2; D034802:RNA-Binding Protein EWS