Molecular dissection of the mechanism utilized by the EWS/FLI oncogene to influence the morphology and behavior of Ewing sarcoma cells

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Title Molecular dissection of the mechanism utilized by the EWS/FLI oncogene to influence the morphology and behavior of Ewing sarcoma cells
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Chaturvedi, Aashi
Date 2013-08
Description Ewing sarcoma is a devastating pediatric tumor that is particularly aggressive and highly metastatic. The current treatment regimen for this malignancy is aggressive, invasive and toxic, but with limited success. Treatment of metastatic or relapsed Ewing sarcoma is even more dismal with a low 5-year patient survival. My research is focused on identifying new mechanisms that could explain early and extensive metastasis in Ewing sarcoma potentially enabling better disease outcome in the future. In the majority of Ewing sarcoma cases, the causal oncoprotein EWS/FLI develops from the reciprocal chromosomal translocation t(11;22)(q24;q12). For this dissertation, I analyzed the effect of EWS/FLI oncoprotein on the cellular behavior of multiple patient-derived Ewing sarcoma cell lines, and discovered that EWS/FLI compromises the cytoskeletal framework of cells. As a result, Ewing sarcoma cells display small round cell morphology and low cellular adhesion. I further show that these EWS/FLI-dependent changes in cell behavior in vitro are pertinent to tumor cell behavior in vivo and could provide relevant insight into the cell of origin for Ewing sarcoma. Based on these observations, I suggest a new model where the inciting oncogenic event could affect tumor cell adhesion to permit early dissemination of tumor cells or increased colonization of tumor cells at a secondary site, to explain early metastasis of tumor cells. In this dissertation the analysis of the EWS/FLI transcriptome, revealed that focal adhesion proteins, extracellular matrix components, and actin cytoskeletal modulators were most downregulated by EWS/FLI expression. Two focal adhesion proteins namely iv zyxin and the fibronectin receptor α5 integrin were shown to play vital roles in modulating Ewing sarcoma cell morphology, cytoskeletal structure, spreading and adhesion. To adequately study the tumor progression and metastasis of Ewing sarcoma, I developed an intratibial orthotopic mouse model. The Ewing sarcoma tumors grew aggressively in mice and spontaneously metastasized from the tibia to lungs and other bones. This model system recapitulates key features pertinent to the human disease. Taken together, the work described in this dissertation reveals the important role of EWS/FLI mediated downregulation of adhesion proteins in modulating essential cellular features, such as cell adhesion and cytoskeletal structure, to govern oncogenic transformation and metastasis.
Type Text
Publisher University of Utah
Subject MESH Sarcoma, Ewing; Bone Neoplasms; Cytoskeleton; Neoplasm Metastasis; Focal Adhesions; Cell Adhesion; Zyxin; Translocation, Genetic; Oncogenes; Down-Regulation; Mesenchymal Stromal Cells; RNA-Binding Protein EWS; Gene Expression Regulation, Neoplastic; Oncogene Proteins, Fusion; Transcription Factors; Transcription, Genetic
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Molecular Dissction of the Mechanism Utilized by the EWS/FLI Oncogene to Influence the Morphology and Behavior of Ewing Sarcoma Cells
Rights Management Copyright © Aashi Chaturvedi 2013
Format application/pdf
Format Medium application/pdf
Format Extent 11,049,836 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s63b97c4
Setname ir_etd
ID 196622
Reference URL https://collections.lib.utah.edu/ark:/87278/s63b97c4
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