Description du projet
La résistance à la transformation oncogénique
Les cellules cancéreuses émergent d’une combinaison d’altérations épigénétiques et génétiques des cellules normales qui favorisent la transformation. Toutefois, les signaux oncogéniques peuvent être bénins pour certaines cellules, ce qui indique l’existence d’un mécanisme protégeant de la transformation cellulaire. En utilisant la drosophile comme modèle, les scientifiques du projet OncoResist, financé par l’UE, étudieront la prolifération des cellules épithéliales dans l’œil à la suite d’une signalisation anormale de la voie Hippo. Les travaux seront axés sur les modifications du paysage nucléaire, telles que l’accessibilité de la chromatine et le rôle des ARN longs non codants. La description de ce mécanisme protecteur ouvrira de nouvelles voies dans les recherches contre le cancer.
Objectif
Oncogenesis is a complex multi-step process that involves the combination of genetic and epigenetic alterations for normal cells to turn into cancerous cells. Remarkably, while some strong oncogenic signals can promote transformation in some cell states, they are completely innocuous to other cell types.
My aim is to study this poorly understood phenomena, being my current hypothesis, that intrinsic cell state transformation protection mechanisms are likely to exist.
I will use the Drosophila eye primordium epithelium, as I have previously observed that whereas committed epithelial cells over-proliferate in response to abnormal Hippo signalling, undifferentiated progenitor cells are resistant to this transformation.
To molecularly define such resilience to oncogenesis, the gene expression and chromatin accessibility profile of these two cell populations were compared. My preliminary results showed that the chromatin accessibility profile differed significantly and suggested that some pioneer transcription factors primed cells to respond to Hippo signalling. Moreover, I observed that non-coding RNAs were differentially expressed between these two cell populations. In particular, some long non-coding RNAs (lncRNAs), a class of molecules that were recently described as regulators of oncogenic signals, were particularly enriched in the progenitor cell population.
More specifically, I aim to address two main questions:
1 - Is the nuclear landscape (chromatin accessibility and TFs combinations) important to control the response to high oncogenic signals? And how much of this response relies on the activity of pioneer transcription factors?
2 - What is the role of the lncRNAs in controlling cellular response to Hippo signalling?
A better understanding of the intrinsic cell state protective mechanisms against transformation is likely to open important new therapeutic approaches for cancer.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
3810-193 Aveiro
Portugal