Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ASCL1

  1. Anna E Hakes
  2. Andrea H Brand  Is a corresponding author
  1. University of Cambridge, United Kingdom

Abstract

Understanding the sequence of events leading to cancer relies in large part upon identifying the tumour cell of origin. Glioblastoma is the most malignant brain cancer but the early stages of disease progression remain elusive. Neural lineages have been implicated as cells of origin, as have glia. Interestingly, high levels of the neural stem cell regulator TLX correlate with poor patient prognosis. Here we show that high levels of the Drosophila TLX homologue, Tailless, initiate tumourigenesis by reverting intermediate neural progenitors to a stem cell state. Strikingly, we could block tumour formation completely by re-expressing Asense (homologue of human ASCL1), which we show is a direct target of Tailless. Our results predict that expression of TLX and ASCL1 should be mutually exclusive in glioblastoma, which was verified in single-cell RNA-seq of human glioblastoma samples. Counteracting high TLX is a potential therapeutic strategy for suppressing tumours originating from intermediate progenitor cells.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Anna E Hakes

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8664-1014
  2. Andrea H Brand

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    a.brand@gurdon.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2089-6954

Funding

Wellcome (103792)

  • Andrea H Brand

Royal Society

  • Andrea H Brand

Wellcome (102454)

  • Anna E Hakes

Wellcome (092096)

  • Andrea H Brand

Cancer Research UK (C6946/A14492)

  • Andrea H Brand

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Claude Desplan, New York University, United States

Version history

  1. Received: November 6, 2019
  2. Accepted: February 19, 2020
  3. Accepted Manuscript published: February 19, 2020 (version 1)
  4. Version of Record published: March 5, 2020 (version 2)

Copyright

© 2020, Hakes & Brand

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Anna E Hakes
  2. Andrea H Brand
(2020)
Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ASCL1
eLife 9:e53377.
https://doi.org/10.7554/eLife.53377

Share this article

https://doi.org/10.7554/eLife.53377

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