Abstract B01: Molecular evolutionary process of malignant glioma
Authors: Rui P. Galvao, Susan Bassham, Thomas C. Nelson, Jason Sydes, Lauren K. Rosenfeld, William A. Cresko, Hui Zong
Journal: Cancer Research (2015)

Abstract Malignant gliomas are devastating, incurable brain tumors, with a bleak prognosis that improved little over the past decades. Many studies have been published describing genomic and transcriptomic alterations in malignant, fully formed gliomas. However, little is known of what takes place before the malignant stage, even though transformation of a normal cell into cancer is a multi-step process and, by the malignant stage, tumor cells have become very different from their original, untransformed ancestry. To gain insight into the driving forces of glioma and develop effective treatments, one must understand the entire process of tumorigenesis, for which it will be necessary to directly characterize the cell of origin of glioma at multiple time points throughout gliomagenesis. We recently identified adult oligodendrocyte precursor cells (OPCs) as a cell of origin for malignant gliomas using a genetic mouse model that induces mutations in p53 and NF1, two of the most frequently mutated genes in human glioblastoma [Galvao et al., 2014, PNAS]. To ensure the introduction of mutations into adult but not neonatal OPCs, we used NG2-CreER that can specifically induce loxP-mediated recombination upon the administration of tamoxifen. Time course analysis revealed several distinct stages of gliomagenesis, starting with a rapid but transient hyper-proliferation shortly after tamoxifen administration, followed by a long dormancy period and ending with malignant transformation. To further investigate the molecular changes during the pre-transforming stages, using the same mouse model, we developed a procedure based on laser capture microdissection to collect OPCs from the adult brain at distinct stages during gliomagenesis. We then used RNA sequencing to gain mechanistic insight into the successive stages of gliomagenesis. Our results show that, compared to tumor OPCs, the gene expression profile of pre-transforming mutant OPCs remains similar to that of wild-type OPCs, indicating that most transcriptional changes occur at the final transformation step. Interestingly, careful analysis revealed expression changes in hundreds of genes shortly after p53/NF1 mutagenesis. Using bioinformatics tools such as Gene Ontology (GO) terms, Gene Set Enrichment Analysis (GSEA) and Signaling Pathway Impact Analysis (SPIA), we are currently identifying the signaling pathways most affected at each time point to gain a better understanding of the molecular evolution from mutant OPCs to malignant glioma, which could provide critical insights on how to halt or even revert that process. Citation Format: Rui P. Galvao, Susan Bassham, Thomas C. Nelson, Jason Sydes, Lauren K. Rosenfeld, William A. Cresko, Hui Zong. Molecular evolutionary process of malignant glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B01.