Oncotarget

Research Papers:

Mouse genetic background influences whether HrasG12V expression plus Cdkn2a knockdown causes angiosarcoma or undifferentiated pleomorphic sarcoma

Laura P. Brandt, Joachim Albers, Tomas Hejhal, Svende Pfundstein, Ana Filipa Gonçalves, Antonella Catalano, Peter J. Wild and Ian J. Frew _

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Oncotarget. 2018; 9:19753-19766. https://doi.org/10.18632/oncotarget.24831

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Abstract

Laura P. Brandt1,2, Joachim Albers1, Tomas Hejhal1, Svende Pfundstein1,3, Ana Filipa Gonçalves1, Antonella Catalano1,6, Peter J. Wild4 and Ian J. Frew1,2,5,6

1Institute of Physiology, University of Zurich, Zurich, Switzerland

2Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

3Zurich Integrative Rodent Physiology, University of Zurich, Zurich, Switzerland

4Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

5BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany

6Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany

Correspondence to:

Ian J. Frew, email: [email protected]

Keywords: angiosarcoma; undifferentiated pleomorphic sarcoma; MuLE lentivirus; H-Ras; mouse model

Received: March 22, 2017     Accepted: February 28, 2018     Published: April 13, 2018

ABSTRACT

Soft tissue sarcomas are rare mesenchymal tumours accounting for 1% of adult malignancies and are fatal in approximately one third of patients. Two of the most aggressive and lethal forms of soft tissue sarcomas are angiosarcomas and undifferentiated pleomorphic sarcomas (UPS). To examine sarcoma-relevant molecular pathways, we employed a lentiviral gene regulatory system to attempt to generate in vivo models that reflect common molecular alterations of human angiosarcoma and UPS. Mice were intraveneously injected with MuLE lentiviruses expressing combinations of shRNA against Cdkn2a, Trp53, Tsc2 and Pten with or without expression of HrasG12V, PIK3CAH1047R or Myc. The systemic injection of an ecotropic lentivirus expressing oncogenic HrasG12V together with the knockdown of Cdkn2a or Trp53 was sufficient to initiate angiosarcoma and/or UPS development, providing a flexible system to generate autochthonous mouse models of these diseases. Unexpectedly, different mouse strains developed different types of sarcoma in response to identical genetic drivers, implicating genetic background as a contributor to the genesis and spectrum of sarcomas.


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