Genomic and nuclear organizational changes in chemotherapy-resistant rhabdomyosarcoma cells
Rhabdomyosarcoma is a pediatric tumor of skeletal muscle that has used essentially the same chemotherapy drugs for treatment for decades. Despite attempts to improve the treatment, patients with disease recurrence still have relatively poor survival. Some rhabdomyosarcoma possess a ‘fusion’ between two genes that not only controls much of its biology, but also causes worse survival. In fact, in patients with metastatic or recurrent tumors that have the gene fusion, survival is <10%. One of the ways that researchers have attempted to improve our treatment of these patients is to try to understand how tumor cells become resistant to chemotherapy drugs – a major issue in patients with recurrent disease. The goal of such studies is typically to understand the drug resistance well enough to identify a new way to make the cells easier to kill with chemotherapy. Many of the studies on chemotherapy resistance in rhabdomyosarcoma have focused on identifying individual genes that cause resistance, and have compared cells that are very resistant to chemotherapy to those that are not resistant at all. However, there is also reason to believe that rhabdomyosarcoma tumor cells are deeply affected not just by individual genes, but by the way the parts of the cell nucleus – the control center of the cell – are organized. This suggests that we can gain new understanding of chemotherapy resistance if we understand the changes that occur in the organization of the nucleus while rhabdomyosarcoma cells are exposed to chemotherapy and become resistant to it.
Dr. MacQuarrie’s project seeks to understand chemotherapy resistance in rhabdomyosarcoma cells: 1) at the level of the organization of their nucleus and 2) over time, rather than just comparing cells with no resistance to those that are very resistant. His project will search for differences in various aspects of organization of the nucleus, and then link those differences directly to the ability of tumor cells to survive chemotherapy treatment. By taking that approach, he aims to find one - or more - new approaches to making the cells more vulnerable to chemotherapy. He will use multiple types of rhabdomyosarcoma cells he can grow in dishes – focusing especially on fusion-positive cells, since their survival is so poor when they re-occur – and study the changes in their nuclear organization while he exposes them to slowly increasing amounts of chemotherapy drugs. Among the techniques he will use to understand their organization is one called PWS (for Partial Wave Spectroscopic) microscopy. This technique utilizes a special microscope that was developed by Dr. MacQuarrie’s scientific mentor, and has been used successfully to advance understanding of adult tumors – including understanding of their resistance to chemotherapy - but has not yet been used in a pediatric tumor like rhabdomyosarcoma. By using tools like PWS microscopy, and others that specifically look at organization and not just at individual genes, Dr. MacQuarrie aims to both further our understanding of why chemotherapy resistance occurs, and identify a new way to overcome it.
