Despite advances in modern chemotherapy, survival for patients with metastatic or relapsed Ewing sarcoma (ES) remains dismally low. In order to improve outcomes, it is necessary that we understand the molecular mechanisms that promote aggressive disease. It is our hypothesis that ES cells exhibit phenotypic plasticity, and that the phenotype can be influenced by selective pressures in the tumor microenvironment. To test this hypothesis, we have proposed two specific aims. First, we will assess the contribution of the extracellular ligand R-spondin (RSPO) to the metastatic phenotype. RSPO interacts with the surface receptor and stem cell marker LGR5. This interaction promotes canonical Wnt signaling. Based on our preliminary studies, we hypothesize that potentiation of Wnt signaling by RSPO will promote metastasis. In our second aim, we will elucidate the contribution of oncogenic EWS/ETS fusion proteins to the output of Wnt signaling in ES. EWS/ETS fusion proteins are the result of chromosomal translocations that occur in the majority of ES tumors. These fusion proteins interfere with Wnt signaling. We have observed that extracellular microenvironmental factors can alter EWS/ETS levels. It is our hypothesis that these changes in the microenvironment can alter EWS/ETS levels and thus contribute to regulation of Wnt activity. Through these studies, we expect to elucidate the specific role of RSPO/LGR5/Wnt signaling, and how this signaling is influenced by EWS/ETS fusion proteins. At the completion of these studies, we will have gained further insight into the molecular mechanisms that drive aggressive disease, and how these mechanisms can be exploited for therapy.

Public Health Relevance

Ewing sarcoma is a deadly cancer that mainly affects children and adolescents, and patients with metastasis have an especially poor chance of survival. This proposal aims to identify molecular mechanisms that contribute to metastasis in this disease. In particular, we plan to elucidate the specific role of LGR5/Wnt signaling and its interactions with EWS/ETS fusion proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA183276-01
Application #
8644392
Study Section
Special Emphasis Panel (ZRG1-F09B-P (20))
Program Officer
Damico, Mark W
Project Start
2014-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$32,671
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109