The Role of MST1 in Non-canonical Hippo Signaling in Rhabdomyosarcoma

Background

While overall pediatric cancer patient survival rates have significantly improved over the past 40 years, poor prognosis persists in the aggressive pediatric cancer, alveolar rhabdomyosarcoma (aRMS). aRMS survival rates for high risk groups have not significantly improved in decades, due to an incomplete understanding of the underlying disease mechanisms. Many aRMS tumors harbor an aRMS-specific gene mutation, known as PAX3-FOXO1. However, using experimental approaches, this mutation alone is not sufficient for tumor formation. This means that additional changes must occur within the cancer cell for aRMS to occur.

Project Goal

Using genetic modeling approaches in the laboratory, we have identified a new tumor-causing mechanism in aRMS. This mechanism involves a tumor-preventing protein called MST1 becoming inactivated. This inactivation, in combination with PAX3-FOXO1 expression, causes aRMS tumors in a mouse model. Using this model, we can design new aRMS therapeutic approaches. In this project, I will determine how MST1 inhibition leads to tumor initiation and how to target MST1 pathways therapeutically.  The ALSF "A" Award would allow me to begin my career as an independent investigator focused on aRMS research. My future laboratory will study the underlying cancer-causing aRMS mechanisms and identify novel approaches to treat this deadly disease.