Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice
Open Access
- 23 January 2022
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 257 (1), 109-124
- https://doi.org/10.1002/path.5873
Abstract
Angiosarcomas are aggressive vascular sarcomas that arise from endothelial cells and have an extremely poor prognosis. Because of the rarity of angiosarcoma, knowledge of molecular drivers and optimized treatment strategies are lacking, highlighting the need for in vivo models to study the disease. Previously, we generated genetically engineered mouse models of angiosarcoma driven by aP2-Cre-mediated biallelic loss of Dicer1 or conditional activation of KrasG12D with Cdkn2a loss that histologically and genetically resemble human tumors. Here, we find that DICER1 functions as a potent tumor suppressor and its deletion, in combination with either KRASG12D expression or Cdkn2a loss, is associated with angiosarcoma development. Independent of the genetic driver, the mTOR pathway was activated in all murine angiosarcoma models. Direct activation of the mTOR pathway by conditional deletion of Tsc1 with aP2-Cre resulted in tumors that resemble intermediate grade human kaposiform hemangioendotheliomas indicating that mTOR activation was not sufficient to drive the malignant angiosarcoma phenotype. Genetic dissection of the spectrum of vascular tumors identified genes specifically regulated in the aggressive murine angiosarcomas that are also enriched in human angiosarcoma. The genetic dissection driving the transition across the malignant spectrum of endothelial sarcomas provides an opportunity to identify key determinants of the malignant phenotype, novel therapies for angiosarcoma, and novel in vivo models to further explore angiosarcoma pathogenesis.Funding Information
- American Lebanese Syrian Associated Charities
- National Cancer Institute (P30 CA082709, P30 CA21765, P30CA023168, R01CA216344, R01CA251436)
- V Foundation for Cancer Research
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