Description of the thesis topic

Therapeutic modulation of non-coding RNAs in proliferative diseases: applications in lung cancer and renal fibrosis
Non-coding RNAs (ncRNAs) play a central role in gene expression regulation and in numerous cellular and molecular processes. Their dysregulation is implicated in various pathologies. This doctoral project aims to explore the therapeutic potential of targeting ncRNAs in two distinct contexts: lung cancer and renal fibrosis.
Axis 1: Targeting miR-24-3p in lung adenocarcinomas
MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression. Some miRNAs play a central role in tumorigenesis, acting as oncogenes or tumor suppressors. Our preliminary work has shown that inhibition of miR-24-3p using antisense oligonucleotides (ASOs) in lung adenocarcinoma cells restores apoptosis and sensitivity to cisplatin. These findings suggest that targeting this miRNA could represent a relevant therapeutic strategy in bronchopulmonary cancers. To assess the therapeutic potential and renal safety of this approach, we propose to evaluate the pharmacological effects of ASOs in a mouse model of lung adenocarcinoma (CCSPCre-LSL-KrasG12D model). Overall, these studies will improve our understanding of the role of miRNAs in cancer biology and may ultimately contribute to the development of novel anti-cancer agents.

Axis 2: Targeting the Long Non-Coding RNA DNM3OS in Renal Fibrosis
Alport syndrome (AS) is a hereditary kidney disease characterized by abnormalities in the glomerular basement membrane caused by mutations affecting collagen IV. This pathology leads to progressive fibrosis, often resulting in end-stage renal disease. Our project proposes an innovative approach aimed at blocking or slowing renal fibrosis by targeting the long non-coding RNA DNM3OS, a key regulator of TGF-β-induced myofibroblast activation. The proposed approaches will include: (1) A preclinical murine model (col4a3-/- strain) mimicking the characteristics of AS, to evaluate the effect of DNM3OS inhibition on disease progression; (2) Cellular models to dissect the signaling pathways and molecular mechanisms underlying the effects of DNM3OS targeting; (3) Patient samples from individuals with Alport syndrome to assess the clinical relevance of DNM3OS targeting. This project will clarify the role of DNM3OS in renal fibrosis associated with AS and open the way for a novel therapeutic strategy.

Work Context

The work will take place at the Laboratoire Canther (UMR 9020 CNRS – U1277 Inserm) in Lille, France. The laboratory is associated with the National Centre for Scientific Research (CNRS). Part of the research will be performed in collaboration with hospitals in Lille and abroad. All expenses related to the project will be covered by the laboratory.

Constraints and risks

Short trips within France and abroad are to be expected for conferences and collaborations.