CB-04 EPIGENETIC REGULATION OF GLIOBLASTOMA TUMORIGENICITY: A HYBRID MODEL

Glioblastoma is one of the most devastating of human cancers, with near-uniform fatality within two years of diagnosis. Therapeutic failure is thought to be related to small subpopulations of cells that exhibit the properties of self-renewal and tumorigenicity. Understanding how such subpopulations attain and retain these properties remains a central question in oncology. One fundamental issue is whether tumorigenicity exists within a static population of elite cells or whether the capacity is stochastically acquired. To test these models, we assayed in vitro tumor sphere formation frequencies and in vivo tumor growth of subclones of established glioblastoma lines as well as stem cell lines derived from patients and genetically engineered mouse models. Our findings were best described by a hybrid model that is largely deterministic (elite) but with opportunities for dynamic (stochastic) interchange between non-tumorigenic and tumorigenic states. To identify determinants of tumorigenicity, we performed gene expression profiling of the subclones. Analysis of the data suggested that tumorigenicity in glioblastoma is a dynamic property driven by variations in MYC expression, consistent with the effects of ectopic expression and knockdown. Transitions between tumorigenic and non-tumorigenic cell states were associated with changes in histone modifications at the MYC locus, suggesting epigenetic regulation. The role of MYC as a "tumorigenicity gene" is fundamentally distinct from those previously ascribed to oncogenes. The model suggests the need for therapeutic strategies that disrupt the dynamic transition between cell states.