Guided by the genetics of human angiosarcomas and UPS tumours, we functionally tested the contributions of the candidate sarcoma tumour suppressors Cdkn2a, Trp53, Tsc2 and Pten and the candidate oncogenes HrasG12V, PIK3CAH1047R or Myc. We discovered that the systemic injection of ecotropic lentiviruses expressing oncogenic HrasG12V together with the knockdown of Cdkn2a or Trp53 was sufficient to initiate angiosarcoma formation in multiple organs in SCID/beige mice. Here, TP53 is linked to angiosarcoma.