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

Abstract
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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

(2019) single cell RNA-seq analysis of adult and paediatric IDH-wildtype Glioblastomas
NCBI Gene Expression Omnibus,GSE131928.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE131928

Article and author information

Author details

Anna E Hakes

The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8664-1014
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.

"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.

Copyright

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.