Angiosarcomas are tumors arising from transformation of vascular endothelial cells. They are highly invasive, have low survival rates and progress rapidly to a terminal state. While spontaneous disease is rare (2% of sarcomas), angiosarcomas are a recognized complication of breast trauma and cancer radiotherapy, with subsequent potential mortality due to this secondary disease. Evidence for genetic and environmental factors underlying the emergence of vascular tumors is limited. Unlike other tumors, there are no animal models in which to study its biology or explore potential treatment modalities. The current standard of care for vascular tumors involves surgical resection alone. Chemotherapy and radiation do not improve survival. Therefore, current treatment will not change unless information related to the basic mechanisms of disease are addressed. The long term goal of the current line of investigation is to identify genetic, cellular and molecular mechanisms underlying the development of angiosarcomas. Using a transposon screen in mice, we have identified 81 genes that are associated with the emergence of vascular anomalies, angiosarcomas, and cavernous tumors. Some of these genes were also found mutated in human angiosarcomas, as per findings from exome sequencing. Subsets of these genes have been implicated in cytoskeletal dynamics, proliferation and signaling. Other subsets in the regulation of p53 and radiation sensitivity. Replication of some of these mutations in normal endothelium elicits transformation, including anchorage-independent growth in soft agar assays and tumor growth in nude mice. These features provide the background and rationale to expand this research and explore the mechanisms that trigger endothelial transformation. In this grant application, we propose experiments to explore the biology of a subset of 3 genes that appear to work together as causative genes for angiosarcoma and to clarify the molecular mechanisms that lead to deregulated proliferation and invasiveness. The central hypothesis is that endothelial mutations in RASA1 predispose, but are only transforming if either ELMO1 and / or ZMIZ1 are also mutated. In combination these 3 genes work together to mediate loss of cell-cycle control and highly invasive properties typical of angiosarcomas. To test this hypothesis we propose: 1) To characterize critical molecular interactions and genetic interdependencies required for endothelial transformation in angiosarcoma and 2) To define the contribution of RASA1 in deregulated endothelial proliferation. Considering the poor survival rate of individuals with vascular tumors and the rising incidence of this tumor type as a consequence of radiation therapy, we believe that research aimed at understanding the mechanisms that trigger and sustain this disease are of paramount relevance.
Despite their low frequency, vascular tumors are amongst the most fatal and/or highly debilitating of cancers. Available treatments fail in over 50% of cases and current advances in this area limited. Experiments outlined in this proposal aim to identify genetic features responsible for the emergence of vascular tumors with the ultimate goal to develop novel therapeutic approaches for this highly invasive malignant disease.
|Ziyad, Safiyyah; Riordan, Jesse D; Cavanaugh, Ann M et al. (2018) A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis. Cell Rep 22:1211-1224|
|Hilfenhaus, Georg; Nguyen, Dai Phuong; Freshman, Jonathan et al. (2018) Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers. J Cell Biol 217:2813-2830|