Identification of Hypoxia-induced Pathways Driving Ewing sarcoma Metastases

Background

Treatment of metastatic Ewing sarcoma (ES) remains an unsolved clinical problem, with a 3-year event free survival at 27% for patients with metastases at diagnosis. Tumor hypoxia is one of the few known metastatic factors in ES, yet the exact pathways underlying its actions remain unknown.

To address this problem, we created a unique model of hypoxia-induced ES metastases by blocking the blood supply to the primary tumor growing in the hind limb of the mouse. Using this approach, we demonstrated an increase in the metastatic properties of ES tumors evidenced by increased frequency of metastases and dissemination to multiple locations.

During the course of these studies, we have collected tissue samples and developed cell lines from control and hypoxic primary tumors, as well as their corresponding metastases. Importantly, we have previously shown that cells derived from such metastases have enhanced metastatic properties upon re-introduction to animals, proving their ability to preserve malignant properties.

Project Goal

The goal of the current project is to identify the mechanisms and pathways driving hypoxia-induced metastases. To this end, we will compare functional properties and metabolomic profiles of the cells derived from normoxic and hypoxic tumors and their corresponding metastases to identify pathways that are altered in hypoxic, metastatic cells. These results will be subsequently validated in tissue samples derived directly from the experimental animals. Lastly, we will determine if blocking these candidate pathways will inhibit metastatic phenotype of the hypoxic tumor cells.