Mechanisms of Ewing sarcoma development and therapeutic resistance Public Deposited

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  • March 20, 2019
Creator
  • Gomez, Nicholas
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Many large scale consortia have begun to use high-throughput sequencing technologies to identify key mutations and pathways involved in the etiology of cancers. Identification of specific mutations within tumors can also influence patient-directed therapeutic decisions. Recent evidence implicates the insulin-like growth factor pathway in development of Ewing Sarcoma, a highly malignant bone and soft tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. All cases of Ewing sarcoma are characterized by a translocation between EWSR1 and an ETS-family transcription factor where 85% of the cases result in the EWSR1-FLI1 t(11;22)(q24:q12). This novel transcription factor is retargeted to a subset of repetitive elements in a cell-type specific manner by a previously unknown mechanism. In the chapters that follow, we describe the cellular consequences of PTEN loss in Ewing sarcoma as well as a mechanism for EWSR1-FLI1 retargeting. We demonstrate that Ewing sarcoma cells with PTEN loss exhibited increased transformative properties, as well as reciprocal sensitivity to IGF-1R and mTOR inhibition, therapies currently undergoing testing in clinical trials. In addition, our studies also describe a novel chromatin environment of stem cells in which repetitive elements are enriched in accessible chromatin. Strikingly, a subset of accessible repetitive elements in stem cells is associated with Ewing Sarcoma development. Repetitive elements exhibiting the greatest FAIRE signal in stem cells, is associated with increased EWSR1-FLI1 binding, suggesting the chromatin environment of stem cells is primed for oncogenesis. Taken together, these studies expand our knowledge of Ewing sarcoma etiology and provide a potential mechanism for therapy resistance. This work serves as the foundation for both expanded preclinical and clinical research for future targeted therapies in Ewing sarcoma.
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  • In Copyright
Advisor
  • Duronio, Robert
  • Davis, Ian
  • Kim, William
  • Bautch, Victoria
  • Mohlke, Karen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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