"Antitumour therapy targeting the RNA interference pathway (2022-12-PIAGGIO_POIRIER)" project details

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General information

Application closed

2022-12-PIAGGIO_POIRIER

Cancer; transposable elements; RNA interference; Antitumour immunity; Targeted therapy.

Antitumour therapy targeting the RNA interference pathway

Director(s) and team

Eliane Piaggio & Enzo Poirier

Translational immunotherapy and Stem Cell Immunity

Abstract

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 malignancies.   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 therapy.

Requirements to apply for the PhD thesis project

Applicants should show a strong motivation to learn and improve, as well as a sense of initiative and solid creative thinking. Background in cell biology is strongly recommended. Experience in mouse experimentation is not compulsory but will be considered preferable.