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19.02.20 Brand lab use lineage tracing to identify brain tumour cell of origin

last modified Mar 31, 2020 03:41 PM
In their new study, Hakes and Brand show that high levels of Tailless/TLX drive tumour initiation by reverting intermediate progenitors to neural stem cells. In addition to identifying the cell fate changes that occur upon high expression of Tailless/TLX, they were able to prevent tumour formation and restore neurogenesis by re-expressing the proneural gene asense/ASCL1. Their results potentially implicate intermediate progenitors as one of the cells of origin in TLX-positive glioblastomas, an aggressive and lethal brain tumour.
19.02.20 Brand lab use lineage tracing to identify brain tumour cell of origin

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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Read more about research in the Brand lab.

Watch Andrea Brand describe her research on YouTube.

 

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