Research
Epitranscriptomics & Cancer Adaptation : A.David

Chemical modifications in RNA, known since the 1970s, gained biological significance through advances in mass spectrometry and NGS. These epigenetic markers, alongside those in chromatin, regulate gene expression (splicing, stability, translation) and key biological functions. Over 150 RNA modifications have been identified (Figure 1), reflecting a dynamic RNA metabolism that reveals cellular or tissue states in real time. Beyond their functional roles, these modifications hold promise for personalized medicine, aiding in disease diagnosis and therapeutic strategies. Studies link deregulation of RNA epigenetic effectors—classified as "writers," "erasers," and "readers"—to human pathologies, particularly cancer. These effectors contribute to tumor progression, dissemination, resistance to therapies, and recurrence, making them crucial targets for understanding and treating disease.

Three axes of research are developed by our team, in synergy with the SMART consortium, the GDR “RNA”, the TRANSLACORE European network and clinical teams at the ICM and CHU.

Axis 1 : EpiTransDiaG - Leveraging the expitranscriptome for cancer diagnosis and screening (Leaders: A. David & S. Quesada)

This axis combines mass spectrometry with machine learning to convert the chemical information contained in RNA samples extracted from cohorts of cancer patients (tissues and biofluids) into epitranscriptomic signature(s) that could be exploited for diagnosis and prognosis. To this end, an experimental and analytical pipeline has been established in a platform specialized in the development of clinical biomarkers (PPC-SMART). EpiTransDiaG exploits the extreme sensitivity of mass spectrometry and the power of artificial intelligence to predict the presence of disease from very small sample quantities (2 drops of blood), within a few hours, and with formidable efficiency. In partnership with ICM and CHU teams, this project is the subject of a SATT maturation program (2023-25).

Axis 2 : SCoRE - Studying the impact of the epitranscriptome on cancer cell adaptation (Leaders: A. David & C. Planque)

Based on clinical data from the first axis, the second axis, SCoRE, identifies chemical markers "functionally" involved in cancer progression/adaptation, whose enzymatic effectors may represent a potential therapeutic target. Two modifications are currently being studied. First, the N6,2′-O-dimethyladenosine (m⁶A_m), a modification adjacent to the mRNA cap, which is involved in mRNA maturation, stability and translational control. Second, queuosine, an hypermodified nucleoside of bacterial origin found at position 34 (wobble) of four tRNAs and regulating translational efficiency (and fidelity) of corresponding codons.

Axis 3: EpiCure - Designing new therapeutic concepts based on RNA and its chemistry (Leaders: A. David & F. Macari)

The last axis, EpiCure aims to model and design RNA-based therapeutics, in particular inhibitors targeting RNA and epitranscriptome enzymes. This study is being carried out in close collaboration with 3 chemistry teams (M. Duca, ICN; M. Smietana, IBMM; M. Etheve-Quelquejeu, LCBPT). This program also includes the conception of tailored therapeutic mRNA within the framework of the IHU IMMUN4CURE.