Rxivist logo

PI3K Activation In Neural Stem Cells Drives Tumorigenesis Which Can Be Suppressed By Targeting CREB

By Paul M. Daniel, Gulay Filiz, Daniel V. Brown, Michael Christie, Paul M. Waring, Yi Zhang, John M. Haynes, Colin W Pouton, Dustin Flanagan, Elizabeth Vincan, Terrance G. Johns, Karen Montgomery, Wayne A. Phillips, Theo Mantamadiotis

Posted 30 May 2017
bioRxiv DOI: 10.1101/143388 (published DOI: 10.1093/neuonc/noy068)

Hyperactivation of the PI3K signaling is common in human cancers, including gliomas, but the precise role of the pathway in glioma biology remains to be determined. Some limited understanding of PI3K signaling in brain cancer come from studies on neural stem/progenitor cells (NSPCs) where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate NSPC proliferation. To investigate the role for the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a Pik3caH1047A oncogenic mutation and simultaneous deletion of the PI3K negative regulator, Pten, in NSPCs. We show that the expression of a Pik3caH1047A was sufficient to initiate tumorigenesis but that simultaneous loss of Pten, was required for the development of invasive, high-grade glioma. Mutant NSPCs exhibited enhanced neurosphere forming capacity which correlated with increased Wnt signaling. We also show that loss of CREB in Pik3ca-PTEN tumors led to a longer symptom-free survival in mice. Taken together, our findings present a novel mouse model for high-grade glioma with which we demonstrate that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.

Download data

  • Downloaded 587 times
  • Download rankings, all-time:
    • Site-wide: 35,843 out of 118,665
    • In cancer biology: 985 out of 3,753
  • Year to date:
    • Site-wide: 94,047 out of 118,665
  • Since beginning of last month:
    • Site-wide: 98,714 out of 118,665

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News