Mechanisms of LGR5 Regulation and Function in Ewing sarcoma Metastasis
Many, if not all, pediatric tumors arise when gene mutations alter cell behavior to promote cancerous rather than normal growth. In particular, cancer cells hijack the normal differentiation programs of developmentally immature cells, such as stem cells, ultimately driving them to create malignant rather than normal tissues. A key developmental pathway that is frequently disrupted in human cancer cells is called the Wnt pathway. We have discovered that a key regulator of the Wnt pathway, a receptor protein called LGR5, is abnormally over-expressed by some Ewing sarcoma cells. Significantly, cells with high levels of LGR5 adopt migratory and invasive properties, properties that are necessary for metastatic spread of the tumor. Moreover, Ewing sarcoma cells upregulate expression of LGR5 when they are deprived of growth factors, a common scenario that is encountered by cancer cells in a rapidly growing tumor.
The central hypothesis underlying the current proposal is that activation of LGR5 and Wnt signaling promotes the metastatic potential of Ewing sarcoma cells, thereby promoting the spread of a local tumor to distant sites. Unfortunately, despite decades of intensified therapy and advances in supportive care, the outcome for patients with metastatic Ewing sarcoma remains dismal. It is our goal with these studies to determine if LGR5 and Wnt represent key mediators of tumor metastasis and to investigate whether therapeutic targeting of this axis could be used as a novel approach for therapy in patients who are at risk for metastatic progression and relapse.