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.
Highlights
Soft tissue sarcomas are rare mesenchymal malignancies that account for approximately 1% of all cancers
To functionally test the contributions of different candidate driver oncogenes and tumour suppressor genes to the formation of angiosarcoma, we generated a panel of lentiviral vectors based on the MuLE system [10] (Supplementary Figure 1A), to induce genetic alterations that reflect some of the most commonly found alterations of human angiosarcomas
The absence of increased proliferation induced by oncogenic HrasG12V or oncogenic HrasG12V plus Trp53 knockdown is likely to be mediated by the upregulation of p16INK4A protein expression observed in pMSEC cells infected with these vectors (Supplementary Figure 1B) as removal of this putative proliferative barrier by knockdown of Cdkn2a increased cellular proliferation (Supplementary Figure 2A)
Summary
Soft tissue sarcomas are rare mesenchymal malignancies that account for approximately 1% of all cancers. The WHO has defined over 100 different soft tissue sarcoma subtypes named after the tissue that they most closely resemble [1]. Undifferentiated pleomorphic sarcomas (UPS), previously referred to as malignant fibrous histiocytomas (MFH), account for approximately 5% of adult soft tissue sarcomas and represent one of the most common types of high-grade soft tissue sarcoma. Standard treatment options are surgical resection, radiotherapy, and chemotherapy, which in many cases are not curative, highlighting the necessity to develop novel targeted treatments.
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