Functional Characterization Of Oncogenic-Induced Dedifferentiation In Neurons And Astrocytes Using Dp-Seq

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. Using a Cre-inducible lentiviral GBM mouse model we recently showed that gliomas can originate from dedifferentiation of mature neurons and astrocytes. Expression analysis of the known markers (of the differentiated cell-types) showed diminished expression while the expression of the undifferentiated state markers were significantly up-regulated in the dedifferentiated transformed neurons and astrocytes. In this study, we performed whole transcriptome analysis of these cells along with mouse pluripotent embryonic stem cells (mESC), neural stem cells (NSC), neurons and astrocytes to characterize the undifferentiated state of these cells. Our analysis revealed that dedifferentiated cell-types shared traits with neurons and NSCs at the global transcriptome level suggesting that they have retained memory of their cell-of-origin and share markers of undifferentiated cells with NSCs. Functional analysis of the transcriptomics data revealed involvement of the Wnt signaling, cell cycle and the focal adhesion pathways in defining the state of the dedifferentiated cell-types. Our analysis further revealed conservation of a gene interaction network in both dedifferentiated cell-types. This network exhibited a modular architecture, connecting components of the cell cycle pathway to Wnt signaling and the focal adhesion pathways. One of these components, Osteopontin (OPN), also known as Spp1, is highly expressed and secreted by the tumors and dedifferentiated transformed neurons and astrocytes. Attempts to inhibit the action of OPN, either by using a neutralizing antibody or silencing the OPN gene (shRNA), blocked the formation of tumorspheres and diminished their proliferating capacity. We are currently assessing the effects of the inhibition of OPN function in vivo. Further genetic perturbation of additional interacting partners and/or the abolishment of the interactions can help elucidate the regulatory mechanism of this network in maintaining the dedifferentiated state of the transformed neurons and astrocytes. Citation Format: Dinorah Friedmann-Morvinski, Vipul Bhargava, Shakti Gupta, Inder M. Verma, Shankar Subramaniam. Functional characterization of oncogenic-induced dedifferentiation in neurons and astrocytes using DP-seq. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1914. doi:10.1158/1538-7445.AM2014-1914