Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB

Paul M. Daniel, Gulay Filiz, View ORCID ProfileDaniel V. Brown, Michael Christie, Paul M. Waring, Yi Zhang, John M. Haynes, View ORCID ProfileColin Pouton, Dustin Flanagan, Elizabeth Vincan, Terrance G. Johns, Karen Montgomery, View ORCID ProfileWayne A. Phillips, View ORCID ProfileTheo Mantamadiotis
doi: https://doi.org/10.1101/143388
Paul M. Daniel
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gulay Filiz
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel V. Brown
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daniel V. Brown
Michael Christie
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul M. Waring
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yi Zhang
2Stem Cell Biology Group, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John M. Haynes
2Stem Cell Biology Group, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colin Pouton
2Stem Cell Biology Group, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Colin Pouton
Dustin Flanagan
3Molecular Oncology Laboratory, University of Melbourne
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth Vincan
3Molecular Oncology Laboratory, University of Melbourne
4Victorian Infectious Diseases Reference Laboratory, Doherty Institute
5School of Biomedical Sciences, Curtin University, WA, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terrance G. Johns
6Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karen Montgomery
7Cancer Biology and Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wayne A. Phillips
7Cancer Biology and Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
8Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Wayne A. Phillips
Theo Mantamadiotis
1Department of Pathology, School of Biomedical Sciences, University of Melbourne, Parkville, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Theo Mantamadiotis
  • For correspondence: theom@unimelb.edu.au
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted May 30, 2017.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB
Paul M. Daniel, Gulay Filiz, Daniel V. Brown, Michael Christie, Paul M. Waring, Yi Zhang, John M. Haynes, Colin Pouton, Dustin Flanagan, Elizabeth Vincan, Terrance G. Johns, Karen Montgomery, Wayne A. Phillips, Theo Mantamadiotis
bioRxiv 143388; doi: https://doi.org/10.1101/143388
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB
Paul M. Daniel, Gulay Filiz, Daniel V. Brown, Michael Christie, Paul M. Waring, Yi Zhang, John M. Haynes, Colin Pouton, Dustin Flanagan, Elizabeth Vincan, Terrance G. Johns, Karen Montgomery, Wayne A. Phillips, Theo Mantamadiotis
bioRxiv 143388; doi: https://doi.org/10.1101/143388

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (2530)
  • Biochemistry (4972)
  • Bioengineering (3482)
  • Bioinformatics (15212)
  • Biophysics (6897)
  • Cancer Biology (5390)
  • Cell Biology (7738)
  • Clinical Trials (138)
  • Developmental Biology (4530)
  • Ecology (7147)
  • Epidemiology (2059)
  • Evolutionary Biology (10227)
  • Genetics (7512)
  • Genomics (9786)
  • Immunology (4844)
  • Microbiology (13215)
  • Molecular Biology (5138)
  • Neuroscience (29435)
  • Paleontology (203)
  • Pathology (837)
  • Pharmacology and Toxicology (1463)
  • Physiology (2138)
  • Plant Biology (4748)
  • Scientific Communication and Education (1013)
  • Synthetic Biology (1338)
  • Systems Biology (4012)
  • Zoology (768)