A novel mouse model of rhabdomyosarcoma

Rhabdomyosarcoma (RMS), an aggressive childhood cancer, is the most common soft tissue malignancy in children, accounting for 5-10% of all pediatric tumors. The most common form of RMS is the embryonal subtype (eRMS), representing nearly two-thirds of RMSs.  RMS is thought to be initiated from muscle stem cells because the tumor expresses skeletal muscle markers. During the analysis of transgenic mice expressing activated Shh signaling in the brain, we serendipitously discovered that these mice exhibited RMS with 100% incidence. These tumors arose primarily in the head, neck and extremities like those found in RMS patients. Surprisingly, we found that Shh signaling was not activated in muscle stem cells but in novel cells of the skeletal muscles. We propose that these novel cells serve as cell-of-origin for RMS. To test our model, we will characterize these novel cells with respect to different resident cell populations in the skeletal muscle. Additionally, we will determine whether these novel cells are susceptible to tumor formation when Shh signaling pathway is activated using a combination of mouse genetics and transplant methods. Collectively, the proposed study provides an important new tool in the fight against childhood cancer, one that will help build our knowledge regarding the formation of RMS and lay fundamental groundwork for future studies. In addition to addressing fundamental questions regarding the biology of RMS, our model may ultimately be used to develop new ways of screening for and treating the disease.