Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas.

摘要

The goal of this project is to test our hypothesis that cellular context in which tumors initiate may have a dominant role over some oncogene function in determining molecular phenotypes. To test this hypothesis, we proposed to transform neural stem cells (NSCs) and neural progenitor cells (NPCs) by expressing an activated form of Notch1 (N1ICD) or oncogenic PIK3CA (PIK3CA*) in the developing mouse cerebellum, using cell type- specific Cre drivers (En2-Cre for NSCs and Atoh1-creER for NPCs). During this funding period, we were successful in intercrossing N1ICD, En2-Cre, Atoh1-cre, and p53 strains to generate N1ICD;En2-cre;p53-/- and N1ICD;Atoh1-CreER;p53-/- mice. We are currently aging these mice to collect medulloblastomas for molecular analyses. For PIK3CA*-induced models, we first analyzed the effect of PIK3CA* expression in different cellular compartments in the developing brain since this is a new model and the effects of oncogenic PIK3CA* expression in the developing brain is unknown. Our analyses showed that our PIK3CA* transgenic model is functional and that oncogenic PIK3CA* expression in the developing brain affects proliferation and differentiation. We are intercrossing PIK3CA* mice with Atoh1-cre, En2-cre, and p53-/- mice to generate PIK3CA*;Atoh1-CreER;p53-/- and PIK3CA*;Atoh1-CreER;p53-/- mice to generate spontaneous medulloblastomas.