In Vivo Validation of Cell of Origin and Candidate Drivers of Group 4 Medulloblastoma
Abstract
Medulloblastoma is the most common childhood brain tumor and is a major cause of cancer related mortality in children. Although current treatment strategies reach a 60-80 percent 5-year survival rate, a proportion of cases remain unresponsive to therapy and lack more effective treatment options. A significant molecular heterogeneity exists within the medulloblastoma subgroups, especially within Group 4 medulloblastoma (G4-MB), challenging the choice and prediction of response to a particular therapy. Our objective is to define the cell-of-origin and candidate drivers of G4-MB, and to develop pre-clinical mouse models that reflect G4-MB tumorigenesis. We have developed a tumor mouse model that allows us to manipulate early iPSC-derived neuroepithelial stem cells, a cell population suggested as the cell-of-origin for but not limited to G4-MB. Using this model we have shown that the G4-MB candidate drivers SRC and ERBB4 induce tumor formation in TP53WT and TP53mut NESCs. Furthermore we are testing pre-clinical therapies of SRC inhibition in our SRC-ERBB4 tumor-bearing mice and are exploring other genetic G4-MB drivers such as ZMYM3. Our mouse models established here will decipher the yet unknown origin of Group 4 medulloblastoma and inform about basic principles of tumorigenesis in the brain.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1190992
Entities
People
- Christin Schmidt
Organizations
- University of California Regents