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

Published version
Peer-reviewed

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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.

Description

Keywords

D. melanogaster, TLX, dedifferentiation, developmental biology, glioblastoma, neural stem cell, regenerative medicine, stem cells, tailless, tumourigenesis, Animals, Carcinogenesis, Cell Differentiation, Cell Lineage, Cell Transformation, Neoplastic, Drosophila Proteins, Drosophila melanogaster, Female, Glioblastoma, Humans, Male, Nerve Tissue Proteins, Neural Stem Cells, Repressor Proteins, Stem Cells

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

9

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Cancer Research Uk (None)
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (102454/Z/13/Z)
Wellcome Trust (103792/Z/14/Z)