Abstract PR02: Dynamic epigenetic regulation of glioblastoma tumorigenicity through a LSD1-MYC-OLIG2 axis

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 subpopulation 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 the tumorigenicity of single-cell subclones derived from long-terms passaged and primary patient-derived xenograft (PDX) glioblastoma lines. 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 molecular 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 variation in MYC expression, which in turn regulates Olig2 expression, a neural stem cell marker. Ectopic expression of MYC conferred tumorigenicty and MYC silencing abolished tumorigenicity in vitro and in vivo for multiple PDX and GEMM models. Transition between tumorigenic and non-tumorigenic cell states was associated with changes in histone modification at the MYC locus mediated by expression of lysine-specific demethylase 1 (LSD1). The model suggests a critical LSD1-MYC-OLIG2 axis that regulates the dynamic transition between glioblastoma cell states of differing tumorigenicity and unveils a novel framework for glioblastoma therapeutic development. Citation Format: Clark Chen, David Kozono, Jie Li, Masayuki Nitta, Oltea Sampetrean, Kimberly Ng, David Gonda, Deepa S. Kushwaha, Dmitry Merzon, Valya Ramakrishnan, Shan Zhu, Kaya Zhu, Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang-Hyuk Kwon, Keith L. Ligon, Hideyuki Saya, Bob S. Carter, Donald P. Pizzo, Scott R. VandenBerg, Frank Furnari, Webster Cavenee. Dynamic epigenetic regulation of glioblastoma tumorigenicity through a LSD1-MYC-OLIG2 axis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR02.