Polyploidy and Ewing sarcoma Bone Metastases

Background

Treatment of metastatic Ewing’s sarcoma (ES) remains an unsolved clinical problem, with a three-year event free survival at 27% for patients with metastases at diagnosis. The survival is even worse for patients with secondary dissemination to bone, particularly when both bone and pulmonary metastases are present (8-14%). Our laboratory focuses on deciphering the mechanisms governing ES dissemination by studying metastatic processes in animal models. Using this approach, we have discovered that ES tumors with a limited blood supply, which are particularly aggressive in both animal models and patients, often metastasize to bones and contain a high number of large cells with increased chromosome number, so-called “polyploid cells.” Strikingly, these large cells accumulate in sites where a tumor invades bone tissue and metastasize specifically to the bone, when injected to mice. Thus, we hypothesize that these polyploid cells are responsible for bone metastasis.

Project Goal

The goal of this project is to identify potential mechanisms of this phenomenon. To this end, we will determine interactions of polyploid ES cells with cells responsible for bone degradation and formation, as tumor-induced bone destruction is commonly associated with the imbalance between these processes. The analyses will be performed in the tumor tissues derived from the original and polyploid cells, as well as upon co-culture of these tumor cell types and bone cells. This project will provide a foundation for future studies designed to identify molecules promoting bone metastasis in ES and determine if blocking their actions prevents tumor dissemination to the bone.