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Cell Death Dis. 2016 Oct 13;7(10):e2419. doi: 10.1038/cddis.2016.268.

Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.

Author information

1
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
2
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
3
Medical University of Vienna, Vienna, Austria.
4
Center of Physiology and Pharmacology, Vienna, Austria.
5
Clinical Institute of Pathology, Vienna, Austria.
6
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
7
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
8
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
9
Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
10
Department of Bone and Skeletal Research, Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.
11
Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.
12
University of Veterinary Medicine, Vienna, Austria.
13
Institute of Medical Genetics, Vienna, Austria.
14
Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, USA.
15
Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

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.

PMID:
27735950
PMCID:
PMC5133963
DOI:
10.1038/cddis.2016.268
[Indexed for MEDLINE]
Free PMC Article

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