Collective cell invasion of fusion positive rhabdomyosarcoma regulated by PAX3-FOXO1
Rhabdomyosarcoma is the most common type of muscle cancer in children. When this cancer spreads to other parts of the body (a process called metastasis), it becomes much harder to treat, and survival rates drop to as low as 20%. Therefore, understanding how this cancer spreads is crucial for developing better treatments. One type of this cancer, fusion-positive rhabdomyosarcoma (FPRMS), has a special abnormal gene that combines two genes, PAX3 and FOXO1. This type tends to spread more than the other type that doesn't have this fusion gene. We think that this abnormal fusion gene makes the cancer cells more aggressive, causing them to invade nearby tissues and spread more easily. Interestingly, FPRMS spreads by moving in groups rather than individually. These groups have "leader" cells at the front of the tumor mass and "follower" cells behind. The leaders create a path by changing their surroundings, while the followers multiply quickly and push the leaders forward. Their teamwork helps the groups invade efficiently and may increase their ability to spread. We found that the leader cells have lower levels of the fusion gene, while the follower cells have higher levels. This suggests that the fusion gene acts like a switch, deciding which cells become leaders and which become followers, each playing a different role in the cancer's invasion process.
Project Goal:
We have been studying how FPRMS controls the expression of the abnormal fusion gene and how this affects the cancer's ability to invade surrounding tissues. We used simplified “bench” models of tumor masses in the lab to understand these processes. Specifically, we found that FPRMS cancer cells interact closely with the surrounding tissue matrix, called the extracellular matrix (ECM). The ECM works as a scaffold, providing cells with physical support to the tissues. We found that this interaction between the cancer cells and the ECM can change how the fusion gene is expressed, affecting the signals that control cancer cell growth and invasion. This, in turn, influences how likely the cancer isto spread. Our goal is to understand how the ECM changes the expression of the fusion gene and how this determines whether cells become leaders or followers. We will also explore the molecular mechanisms that drive the invasion of FPRMS regulated by the teamwork and identify potential targets for new drugs. Additionally, we will test whether drugs that target these mechanisms that help the teamwork can stop the cancer from spreading. Our findings will help develop new and better treatments to prevent the spread of rhabdomyosarcoma and improve outcomes for children with this serious cancer.
