Medulloblastoma is the most common malignant central nervous system cancer in children. Decades of research have shed light on various molecular differences between cancer cells and nontransformed brain cells, but treatments to target only the tumor are lacking. The Sonic hedgehog (Shh) pathway is frequently mutated in these cancers and primary research indicates this pathway is a driving force in oncogenesis. Treatments that target the Shh pathway have been compromised by new mutations and drug resistance. The central hypothesis of this proposal is that growth-promoting pathways, such as Shh and CXCR4, act in concert to promote tumorigenesis and cell proliferation and that defining the mechanisms of their interaction will yield novel approaches to therapy. The mechanism of Shh-induced CXCR4 surface localization will be deciphered using primary mouse cerebellar granule precursor cells and primary murine medulloblastoma cells. Second, the impact of primary cilia on Shh modulation of CXCR4 function will be investigated. Completion of these aims will address the cross-talk between signal transduction pathways within cancer cells and move the field toward novel treatments which target the multiple dysregulations involved in tumorigenesis. This fellowship application addresses the mission statement of the National Cancer Institute by studying the molecular pathways that must be specifically targeted to better treat medulloblastoma, and possibly, other Shh-regulated tumors. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common malignant brain cancer in children. While long-term survival is high, current treatments cause significant and chronic side effects, necessitating life-long medical care for survivors. The ultimate goal of this research is to improve the treatment for medulloblastoma by defining how two targetable pathways, the sonic hedgehog and CXCR4 pathways, converge to promote medulloblastoma genesis and growth.