Transposable elements (TEs) are sequences
embedded in the genome, which expression is usually repressed by epigenetic
marks to prevent their potential genomic toxicity. When expressed in cancer
cells, subsets of TEs can trigger an inflammatory response which correlates
with increased immune cell infiltration and a better response to immune
checkpoint blockade. In that line, awakening TE expression in cancer cells
using chemical inhibitors is used as a targeted therapy against several
This project focuses on understanding the role
of RNA interference (RNAi) in controlling TE expression, and assessing the
possibility of inhibiting RNAi for antitumour therapy. RNAi is used in
mammalian cells to control mRNA translation via the production of micro-RNAs by
Dicer. In parallel, it acts as an antiviral pathway in stem cells through the
activity of antiviral Dicer (aviD). The RNAi pathway has been involved in
silencing TE expression by guiding the deposition of histone repressive marks.
One arm of the project focuses on understanding how RNAi mediates TE
repression. If canonical Dicer was originally thought to be involved, the
candidate will study the putative role of aviD, recently discovered by Dr.
Poirier. aviD’s control of TEs will be assessed in cancer cells in culture and
in mouse tumour models, such as rhabdoid tumours, in which TE expression
regulates antitumour immunity (study by Drs Piaggio, Bourdeaut and Waterfall).
If aviD proves to be involved in TE silencing, the candidate will implement a small
molecule screen to isolate inhibitors of aviD. In parallel, the candidate will
explore the possibility of broadly inhibiting the RNAi pathway in cancer for
antitumour therapy, using similar approaches.
This project will thus delineate the role of RNAi
in controlling TEs and will assess the use of RNAi inhibitors in antitumour