Ewing's sarcoma is a highly malignant bone-associated cancer of children and young adults that usually expresses the EWS/FLI fusion protein. EWS/FLI is the key oncoprotein in Ewing's sarcoma, and functions as an aberrant transcription factor. We recently demonstrated that EWS/FLI downregulates many more genes than it upregulates, and that a portion of these are directly regulated by EWS/FLI binding. This suggests that the widely-accepted model of EWS/FLI functioning as a transcriptional activator may be incomplete, and that it may act as a transcriptional repressor in some settings. Furthermore, our work identified a number of dysregulated genes that are required for the oncogenic behavior of Ewing's sarcoma cells, but suggested that additional targets remain to be identified. Finally, we made the unexpected discovery that EWS/FLI upregulates some of its targets by binding to GGAA-containing microsatellites. This was surprising because these microsatellites do not conform to known EWS/FLI binding sites, nor have they been previously implicated in cancer development. Based on our preliminary data, we hypothesize that EWS/FLI functions as a transcriptional activator at some loci, and as a repressor at other loci, that both of these functions are required to dysregulate critical target genes to induce oncogenic transformation, and that polymorphisms that effect transcriptional function at these loci modulate Ewing's sarcoma susceptibility or prognosis. Experiments are now proposed to test this hypothesis. The transcriptional repression domain of EWS/FLI will be defined, and its role in both the transcriptional and oncogenic function of EWS/FLI determined. Identification and analysis of genes directly regulated by EWS/FLI using both experimental and computational approaches will allow for the identification of new key targets that are involved in the development of Ewing's sarcoma. Analysis of microsatellites in patients and populations will help to define the role of these elements in disease phenotypes and susceptibility to Ewing's sarcoma. At the completion of these studies, we will have developed a deeper understanding of the mechanistic basis of Ewing's sarcoma and applied it translationally. This may allow for the development of new prognostic or therapeutic approaches to this disease, and may impact on our understanding of other ETS-associated cancers as well.

Public Health Relevance

Many cancers are associated with abnormal ETS proteins, such as prostate cancer, leukemia, breast cancer, and sarcoma. Ewing's sarcoma, with its abnormal ETS protein EWS/FLI, serves as a paradigm to understand the function of ETS proteins in cancer. Thus, understanding the mechanisms by which EWS/FLI causes Ewing's sarcoma may identify new approaches for treating this very aggressive cancer of children and young adults, and may also allow for an improved understanding and treatments of other ETS-associated cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140394-05
Application #
8617248
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$269,911
Indirect Cost
$88,763
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lerman, Daniel M; Monument, Michael J; McIlvaine, Elizabeth et al. (2015) Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 62:759-65
Monument, Michael J; Johnson, Kirsten M; McIlvaine, Elizabeth et al. (2014) Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group. PLoS One 9:e104378
Chaturvedi, Aashi; Hoffman, Laura M; Jensen, Christopher C et al. (2014) Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma. Mol Biol Cell 25:2695-709
Sankar, Savita; Theisen, Emily R; Bearss, Jared et al. (2014) Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res 20:4584-97
Sankar, S; Bell, R; Stephens, B et al. (2013) Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma. Oncogene 32:5089-100
Wiles, Elizabeth T; Lui-Sargent, Bianca; Bell, Russell et al. (2013) BCL11B is up-regulated by EWS/FLI and contributes to the transformed phenotype in Ewing sarcoma. PLoS One 8:e59369
Sankar, Savita; Tanner, Jason M; Bell, Russell et al. (2013) A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma. Mol Cell Biol 33:4448-60
Lessnick, Stephen L; Ladanyi, Marc (2012) Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol 7:145-59
Sankar, Savita; Lessnick, Stephen L (2011) Promiscuous partnerships in Ewing's sarcoma. Cancer Genet 204:351-65
Kowalewski, Ashley A; Randall, R Lor; Lessnick, Stephen L (2011) Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis. Sarcoma 2011:598704

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