Descrizione del progetto
Resistenza alla trasformazione oncogena
Le cellule tumorali emergono da una combinazione di alterazioni genetiche ed epigenetiche in cellule normali, promuovendone la trasformazione. Tuttavia, i segnali oncogeni potrebbero essere innocui per alcune cellule, il che suggerisce l’esistenza di un meccanismo che protegge dalla trasformazione cellulare. Utilizzando la Drosophila come modello, gli scienziati del progetto OncoResist, finanziato dall’UE, esamineranno la proliferazione di cellule epiteliali negli occhi a seguito di una segnalazione Hippo anomala. Il lavoro si concentrerà su cambiamenti nel panorama nucleare quali l’accessibilità della cromatina e il ruolo degli RNA lunghi non codificanti. La delineazione di questo meccanismo protettivo aprirà nuove strade nella ricerca antitumorale.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
3810-193 Aveiro
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