Abstract 1809: Analysis of molecular networks that drive astrocytoma initiation and progression.
Authors: Ruzankina Yaroslava , Kutlu Burak , Wang Sophie , Song Yurong , Householder Deborah , Martin Philip , Baran Maureen , Difilippantonio Simone , Hood Leroy , Van Dyke Terry 
Published: August 2014

High grade astrocytomas, anaplastic astrocytoma and glioblastoma multiforme (GBM) remain incurable in spite of advanced aggressive treatments including surgery, radiation and chemotherapy. To study pathways and mechanisms involved in the development of high grade astrocytomas, we used mouse models wherein key molecular pathways perturbed in human GBMs were inactivated or induced via Cre-driven adult astrocyte-specific system. Inhibition of Rb pathway via expression of T121, a N-terminal fragment of SV40 large T antigen (T: TgGZT121, GFAP-CreERTM) initiated diffuse grade II astrocytoma formation by 2 months after tamoxifen treatment which in some cases developed to grade III pathology 1.5 year after induction. Activation of KRas pathway (TR: TgGZT121, Kras+/lsl-G12D, GFAP-CreERTM) facilitated progression to grade III anaplastic astrocytoma tumor masses 4-5 months post induction which in a few cases developed to grade IV glioblastoma with some features of human disease. Additional PTEN loss or haploinsufficiency (TRPhet: TgGZT121, Kras+/lsl-G12D, PTEN+/fl, GFAP-CreERTM; TRPnull: TgGZT121, Kras+/lsl-G12D, PTENfl/fl, GFAP-CreERTM) led to rapid development of glioblastoma with characteristic features of angiogenesis and necrosis observed in human disease. Transcriptome analyses of GBM in our mouse models showed concordance with highly aggressive mesenchymal and proneural subclasses.

To identify disease-specific gene networks involved in astrocytoma initiation and progression, we analyzed more than 300 brain samples from tamoxifen-induced T, TR, TRPhet and TRPnull mice and corresponding controls at different time points after induction for gene and miRNA expression by microarray and Nanostring technology. The genes that were induced early and gradually increased in expression with tumor grade belonged to several key molecular networks: DNA replication and repair, cell division and chromosome transmission fidelity, cell cycle progression, metabolism, and pathways important for embryonic stem cell biology. Pathways significantly induced at later stages of disease (grades III-IV) included Notch and Wnt signaling, inflammatory response genes, p53 signaling, and RNA processing. Significantly downregulated pathways were related to neuronal development and function. We have confirmed expression of several candidate genes in mouse tumor samples and cell lines derived from low and high grade tumors. Currently we are investigating potential role of the selected candidates in astrocytoma development by in vitro and in vivo functional analysis. In summary, we utilized mouse models to determine global molecular changes during astrocytoma initiation and progression to high grade. These studies are important for understanding the mechanisms of the disease and may facilitate the development of new therapies.

Citation Format: Yaroslava Ruzankina, Burak Kutlu, Sophie Wang, Yurong Song, Deborah Householder, Philip Martin, Maureen Baran, Simone Difilippantonio, Leroy Hood, Terry Van Dyke. Analysis of molecular networks that drive astrocytoma initiation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2013-1809