High levels of Tailless drive tumourigenesis by reverting intermediate progenitors (blue) to neural stem cells (red). Tumour cells are outlined in green.
Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ASCL1
Hakes AE and Brand AH. (2020) Elife 9 pii: e53377.
DOI: 10.7554/eLife.53377.
The underlying mechanisms of glioblastoma initiation and growth have proved challenging to elucidate. This is due, in part, to the extensive molecular heterogeneity of glioblastoma, both between patients and within individual tumours. High levels of the orphan nuclear receptor TLX (also known as NR2E1) have been observed in glioblastoma and shown to correlate with poor patient prognosis.
Hakes and Brand found that high levels of the Drosophila TLX homologue, Tailless (Tll), are sufficient to initiate tumours by directing a cell fate change from intermediate progenitor to neural stem cell. They mapped the genome-wide targets of Tll and identified the proneural gene asense as a direct target of Tll repression, both during development and in tumourigenesis. Strikingly, they were able to completely rescue Tll tumours, and restore normal neurogenesis, by re-expressing asense.
Brand and Hakes hypothesized that the reciprocal relationship between Tll and Asense expression might hold true in glioblastoma. Indeed, they found that expression of TLX and ASCL1 (human counterparts of Tll and Asense) are also mutually exclusive in glioblastoma, suggesting a potentially conserved route to tumourigenesis.
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