Description du projet
Modifications épigénétiques dans la résistance aux médicaments anticancéreux
La résistance aux médicaments contre le cancer représente un défi important pour le traitement. Elle résulte de mutations génétiques, du micro-environnement de la tumeur et de changements épigénétiques. Il est essentiel de mieux comprendre ces mécanismes pour mettre au point des stratégies efficaces permettant de surmonter la résistance et d’améliorer les résultats des traitements anticancéreux. Financé par le Conseil européen de la recherche, le projet EpiResist se concentre sur le rôle des modifications de l’ARN dans la résistance aux médicaments anticancéreux. L’objectif est de développer une méthode pour cartographier les modifications de la N6-méthyladénosine (m6A) au niveau de la cellule unique et de l’appliquer aux cellules du cancer du sein triple négatif afin d’identifier des cibles de résistance. Grâce à une analyse unique, le projet entend dévoiler de nouvelles caractéristiques épigénétiques et identifier des interventions thérapeutiques potentielles dans le domaine de recherche en plein essor de l’épitranscriptomique.
Objectif
Drug resistance is one of the biggest challenges in the clinical management of breast cancer (BC), but the underlying mechanisms are still not fully understood. What we do know is that epigenetic mechanisms play a key role in the adaptation of cancer cells to therapy, which is why they have become a prime field of investigation. Single-cell profiling of epigenetic DNA and histone modifications have already revealed intriguing and actionable insights into tumor heterogeneity. For the most recently discovered epigenetic layer however, which consists of RNA modifications, we have not yet reached single-cell resolution. The exciting potential of RNA modifications to fine-tune the processing and expression of mRNAs is currently an area of intense research termed ‘Epitranscriptomics’ and the most prevalent and best studied of these mRNA modifications, N6-methyladenosine (m6A), has recently been linked to drug resistance in cancer. Our lab has uncovered a new m6A-based layer of dysregulation of a major cancer pathway driving therapy resistance in BC. The ability to study m6A in single cells holds great promise as it would enable us to further delineate tumor heterogeneity and to find novel drug resistance targets that have eluded us so far. I propose to develop a method for streamlined m6A mapping at single-cell resolution (Aim 1), to apply it to triple-negative BC (TNBC) cells driven to chemoresistance in cell culture, mice, and human samples so as to determine uncharted targets of drug resistance (Aim 2), and to disrupt m6A-regulated chemoresistance targets in order to prevent therapy failure (Aim 3). These aims are aligned with my knowledge and skills related to both m6A and drug resistance. This unique and comprehensive analysis of the single-cell m6A methylome will provide invaluable new insights into the unknown epigenetic characteristics of chemoresistance and will pave the way for new therapeutic interventions.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
1050 Bruxelles / Brussel
Belgique